This application is 371 of PCT/JP00/02825 Apr. 28, 2000.
1. Technical Field
The present invention relates to novel cyclic ring compounds, which possess CCR antagonistic actions, particularly a CCR5 antagonistic action, and uses thereof.
2. Background Art
In recent years, inhibitors of HIV (human immunodeficiency virus) protease have been developed as therapeutic agents against AIDS (acquired immunodeficiency syndrome), and the use of these drugs in combination with the two HIV reverse transcriptase inhibitors, which have been heretofore employed, have brought a remarkable progress in the treatment of AIDS, whereas this progress is not yet sufficient for eradicating AIDS, whereby the development of new anti-AIDS drugs, which act by still another mechanism, has been desired.
CD4 has been known for some time as a receptor through which HIV enters the target cells, while G-protein-coupled, seven trans-membrane chemokine receptors called CCR5 and CXCR4 have recently been found out as the second group of receptors for macrophage-trophic HIV and T-cell-trophic HIV, respectively, and it is speculated that these chemokine receptors play essential roles in the establishment of infection and transmission of HIV. In fact, there is a report that people who remained resistant to HIV infection in spite of repeated exposures were found to have homozygous deletion in CCR5 gene. Therefore, CCR5 antagonists are expected to be new anti-HIV drugs, and examples of synthesizing new anilide derivatives possessing the CCR5-antagonistic activity are described in patent applications such as PCT/JP98/05708 (WO99/32100), Japanese Patent Application No. 1998-234388 (WO00/10965) and Japanese Patent Application No. 1998-363404 (PCT/JP99/07148), whereas there have so far been no report on commercialization of CCR5 antagonists as the therapeutic agents against AIDS.
The present invention is to provide novel bicyclic ring compounds, which are useful as the prophylactic and therapeutic agents against HIV infectious diseases, particularly AIDS, on the basis of CCR antagonistic actions, particularly a CCR5 antagonistic action.
As a result of intensive investigations on compounds possessing a CCR5 antagonistic action, the present inventors have found that compounds represented by the following formula (I) or salts thereof (hereinafter, may be designated as compounds (I)) possess clinically desirable, medicinal effects such as exhibition of CCR antagonistic actions, particularly an excellent CCR5 antagonistic action, and the like, completing the present invention on the basis of this finding.
In other words, the present invention relates to:
(1) A compound represented by formula (I)
R1xe2x80x94X1xe2x80x94Wxe2x80x94X2xe2x80x94Z1xe2x80x94Z2xe2x80x94R2
xe2x80x83[wherein R1 indicates a 5- to 6-membered cyclic ring group that may be substituted, X1 indicates a bond or a bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4, W indicates a bivalent group that is represented by formula 
xe2x80x83(wherein each of ring A and ring B indicates a 5- to 7-membered cyclic ring group that may be substituted, each of E1 and E4 indicates the carbon atom that may be substituted or the nitrogen atom that may be substituted, each of E2 and E3 indicates the carbon atom that may be substituted or the nitrogen atom that may be substituted, the sulfur atom that may be oxidized or the oxygen atom and each of a and b indicates to be a single bond or a double bond), X2 indicates a bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4, Z1 indicates a bond or a bivalent cyclic ring group, Z2 indicates a bond or a bivalent cyclic ring group, in which the number of atoms constituting the straight-chain portion is 1 to 4, and R2 indicates (1) an amino group that may be substituted, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxide, (2) a nitrogen-containing, heterocyclic ring group that may be substituted and may contain the sulfur atom or the oxygen atom as a ring-constituting atom, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxide, (3) a group that is bonded via the sulfur atom, (4) a group represented by formula 
xe2x80x83(wherein k indicates 0 or 1, the phosphorus atom may form a phosphonium salt when k is 0, and each of R5xe2x80x2 and R6xe2x80x2 indicates the hydrocarbon atom that may be substituted, the hydroxyl group that may be substituted or an amino group that may be substituted (preferably, the hydrocarbon atom that may be substituted or an amino group that may be substituted; more preferably the hydrocarbon atom that may be substituted) and R5xe2x80x2 and R6xe2x80x2 may bind each other to form a cyclic ring group together with the adjacent phosphorus atom), (5) an amidino group that may be substituted or (6) a guanidino group that may be substituted] [provided that, when a group represented by formula R1xe2x80x94X1xe2x80x94Wxe2x80x94X2xe2x80x94Z1xe2x80x94Z2xe2x80x94 indicates a group represented by formula 
xe2x80x83(wherein R1 indicates the same meaning as described above, Wxe2x80x2 indicates a bivalent group represented by formula 
xe2x80x83(wherein ring Axe2x80x2 indicates a 5- to 6-membered aromatic ring that may be substituted, X indicates the carbon atom that may be substituted, the nitrogen atom that may be substituted, the sulfur atom or the oxygen atom and ring Bxe2x80x2 indicates a 5- to 7-membered ring that may be substituted) and Z indicates a bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4, R2 indicates an amidino group that may be substituted or a guanidino group that may be substituted; when a group represented by formula R1xe2x80x94X1xe2x80x94Wxe2x80x94X2xe2x80x94Z1xe2x80x94Z2xe2x80x94 indicates a group represented by formula 
xe2x80x83(wherein R1 and X1 indicate the same meanings as described above, ring Axe2x80x3 indicates a benzene ring that may be substituted, Q1 indicates a bivalent group, in which ring Bxe2x80x3 forms a 5- to 7-membered ring, Q2 indicates the hydrogen atom, a hydrocarbon group that may be substituted, a heterocyclic ring group that may be substituted and Q3 indicates a bond or a bivalent group), R2 does not indicate a group represented by formula 
xe2x80x83(wherein each of R5xe2x80x3 and R6xe2x80x3 indicates the hydroxyl group that may be substituted and R5xe2x80x3 and R6xe2x80x3 may bind each other to form a cyclic ring group together with the adjacent phosphorus atom)], or salts thereof;
(2) A prodrug of the compound or the salt thereof as described in the above-mentioned item (1);
(3) The compound as described in the above-mentioned item (1), wherein R1 is a group that is formed by removing one hydrogen atom from benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or tetrahydrofuran, each of which may be substituted;
(4) The compound as described in the above-mentioned item (1), wherein X1 is a phenyl that may be substituted;
(5) The compound as described in the above-mentioned item (1), wherein R1 is a bond, xe2x80x94(CH2)axe2x80x2xe2x80x94 [axe2x80x2 indicates an integer of 1 to 4], xe2x80x94(CH2)bxe2x80x2xe2x80x94X3xe2x80x94 [bxe2x80x2 indicates an integer of 0 to 3 and X3 indicates an imino group that may be substituted, the carbonyl group, the oxygen atom or the sulfur atom that may be oxidized], xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94SO2xe2x80x94NHxe2x80x94;
(6) The compound as described in the above-mentioned item (1), wherein X1 is a bond;
(7) The compound as described in the above-mentioned item (1), wherein X1 is xe2x80x94(CH2)bxe2x80x2xe2x80x94X3xe2x80x94 [bxe2x80x2 indicates an integer of 0 to 3, and X3 indicates an imino group that may be substituted, the carbonyl group, the oxygen atom or the sulfur atom that may be oxidized];
(8) The compound as described in the above-mentioned item (1), wherein ring A is furan, thiophene, pyrrole, pyridine, pyran or benzene, each of which may be substituted;
(9) The compound as described in the above-mentioned item (1), wherein ring A is a benzene that may be substituted;
(10) The compound as described in the above-mentioned item (1), wherein ring B is a 5- to 7-membered ring that may be substituted at a substitutable optional position, which is represented by formula 
xe2x80x83[wherein E3 indicates the carbon atom that may be substituted or the nitrogen atom that may be substituted, E4 indicates the carbon atom that may be substituted or the nitrogen atom, b indicates a single bond or a double bond and Y indicates xe2x80x94Yxe2x80x2xe2x80x94(CH2)mxe2x80x2xe2x80x94 (Yxe2x80x2 indicates xe2x80x94S(O)mxe2x80x94 (m indicates an integer of 0 to 2), xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94, and mxe2x80x2 indicates an integer of 0 to 2), xe2x80x94CHxe2x95x90, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Nxe2x95x90CHxe2x80x94];
(11) The compound as described in the above-mentioned item (10), wherein Y indicates xe2x80x94Yxe2x80x2xe2x80x94(CH2)2xe2x80x94 [Yxe2x80x2 indicates xe2x80x94S(O)mxe2x80x94 (m indicates an integer of 0 to 2), xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94];
(12) The compound as described in the above-mentioned item (1), wherein E3 indicates the carbon atom that may be substituted, E4 indicates the carbon atom that may be substituted and b indicates a double bond;
(13) The compound as described in the above-mentioned item (1), wherein X2 is xe2x80x94(CH2)axe2x80x2xe2x80x94 [axe2x80x2 indicates an integer of 1 to 4], xe2x80x94(CH2)bxe2x80x2xe2x80x94X3xe2x80x94 [bxe2x80x2 indicates an integer of 0 to 3, and X3 indicates an imino group that may be substituted, the carbonyl group, the oxygen atom or the sulfur atom that may be oxidized], xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94SO2xe2x80x94NHxe2x80x94;
(14) The compound as described in the above-mentioned item (1), wherein X2 is xe2x80x94COxe2x80x94NHxe2x80x94;
(15) The compound as described in the above-mentioned item (1), wherein Z1 is (1) a bond or (2) a bivalent cyclic ring group that is formed by removing two hydrogen atoms from benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or tetrahydropyran, each of which may be substituted;
(16) The compound as described in the above-mentioned item (1), wherein Z1 is (1) a bond or (2) a bivalent cyclic ring group that is formed by removing two hydrogen atoms from benzene, cyclohexane or piperidine, each of which may be substituted;
(17) The compound as described in the above-mentioned item (1), wherein Z1 is a phenylene that may be substituted;
(18) The compound as described in the above-mentioned item (1), wherein Z2 is a bond or a C1-3 alkylene that may be substituted;
(19) The compound as described in the above-mentioned item (1), wherein Z2 is a bivalent group that has a skeleton represented by xe2x80x94Zxe2x80x2xe2x80x94(CH2)nxe2x80x94 [Zxe2x80x2 indicates xe2x80x94CH(OH)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94, and n indicates an integer of 0 to 2] and may have a substituent at an optional methylene group;
(20) The compound as described in the above-mentioned item (1), wherein Z2 is a bond or a methylene;
(21) The compound as described in the above-mentioned item (1), wherein Z1 is a 6-membered, bicyclic ring group, and Z2 is substituted at the para position of X2;
(22) The compound as described in the above-mentioned item (1), wherein R2 is (1) an amino group that may be substituted, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxide, (2) a nitrogen-containing, heterocyclic ring group that may be substituted and may contain the sulfur atom or the oxygen atom as a ring-constituting atom, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxide, (3) an amidino group that may be substituted or (4) a guanidino group that may be substituted;
(23) The compound as described in the above-mentioned item (1), wherein R2 is an amino group that may be substituted;
(24) The compound as described in the above-mentioned item (1), wherein R2 is an amidino group that may be substituted or a guanidino group that may be substituted;
(25) N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[2-(4-propoxyphenyl)ethoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(3-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(2-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(4-propoxyphenyl)methoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(4-propoxyethoxyphenyl)methoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[3-(4-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide, or salts thereof;
(26) A prodrug of the compound or salt thereof as described in the above-mentioned item (25);
(27) A pharmaceutical composition comprising the compounds or salt thereof as described in the above-mentioned item (1);
(28) A pharmaceutical composition for CCR antagonisms (preferably, a CCR5 antagonism) which comprises a compound represented by formula
R1xe2x80x94X1xe2x80x94Wxe2x80x94X2xe2x80x94Z1xe2x80x94Z2xe2x80x94R2
xe2x80x83[wherein R1 indicates a 5- to 6-membered cyclic ring group that may be substituted, X1 indicates a bond or a bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4, W indicates a bivalent group that is represented by formula 
xe2x80x83(wherein each of ring A and ring B indicates a 5- to 7-membered cyclic ring group that may be substituted, each of E1 and E4 indicates the carbon atom that may be substituted or the nitrogen atom that may be substituted, each of E2 and E3 indicates the carbon atom that may be substituted or the nitrogen atom that may be substituted, the sulfur atom that may be oxidized or the oxygen atom and each of a and b indicates to be a single bond or a double bond), X2 indicates a bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4, Z1 indicates a bond or a bivalent cyclic ring group, Z2 indicates a bond or a bivalent cyclic ring group, in which the number of atoms constituting the straight-chain portion is 1 to 4, and R2 indicates (1) an amino group that may be substituted, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxide, (2) a nitrogen-containing, heterocyclic ring group that may be substituted and may contain the sulfur atom or the oxygen atom as a ring-constituting atom, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxide, (3) a group that bonded via the sulfur atom, (4) a group represented by formula 
xe2x80x83(wherein k indicates 0 or 1, the phosphorus atom may form a phosphonium salt when k is 0, and each of R5xe2x80x2 and R6xe2x80x2 indicates the hydrocarbon atom that may be substituted, the hydroxyl group that may be substituted or an amino group that may be substituted and R5xe2x80x2 and R6xe2x80x2 may bind each other to form a cyclic ring group together with the adjacent phosphorus atom), (5) an amidino group that may be substituted or (6) a guanidino group that may be substituted] [provided that, when a group represented by formula R1xe2x80x94X1xe2x80x94Wxe2x80x94X2xe2x80x94Z1xe2x80x94Z2xe2x80x94 indicates a group represented by formula 
xe2x80x83(wherein R1 indicates the same meaning as described above, Wxe2x80x2 indicates a bivalent group represented by formula 
xe2x80x83(wherein ring Axe2x80x2 indicates a 5- to 6-membered aromatic ring that may be substituted, X indicates the carbon atom that may be substituted, the nitrogen atom that may be substituted, the sulfur atom or the oxygen atom and ring Bxe2x80x2 indicates a 5- to 7-membered ring that may be substituted) and Z indicates a bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4), R2 indicates an amidino group that may be substituted or a guanidino group that may be substituted], or salts thereof;
(29) The composition as described in the above-mentioned item (28) which is a prophylactic/therapeutic agent of HIV infectious diseases;
(30) The composition as described in the above-mentioned item (28) which is a prophylactic/therapeutic agent of AIDS;
(31) The composition as described in the above-mentioned item (28) which is a depressant against the pathologic progress of AIDS;
(32) The composition as described in the above-mentioned item (29) which is in combination with a protease inhibitor and/or a reverse transcriptase inhibitor;
(33) The composition as described in the above-mentioned item (32), wherein the reverse transcriptase inhibitor is zidovudine, didanosine, zalcitabine, lamivudine, stavudine, nevirapine, delavirdine, efavirenz or abacavir;
(34) The composition as described in the above-mentioned item (32), wherein the protease inhibitor is saquinavir, ritonavir, indinavir, amprenavir or nelfinavir;
(35) Use of a compound represented by formula
R1xe2x80x94X1xe2x80x94Wxe2x80x94X2xe2x80x94Z1xe2x80x94Z2xe2x80x94R2
xe2x80x83[wherein R1 indicates a 5- to 6-membered cyclic ring group that may be substituted, X1 indicates a bond or a bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4, W indicates a bivalent group that is represented by formula 
xe2x80x83(wherein each of ring A and ring B indicates a 5- to 7-membered cyclic ring group that may be substituted, each of E1 and E4 indicates the carbon atom that may be substituted or the nitrogen atom that may be substituted, each of E2 and E3 indicates the carbon atom that may be substituted or the nitrogen atom that may be substituted, the sulfur atom that may be oxidized or the oxygen atom and each of a and b indicates to be a single bond or a double bond), X2 indicates a bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4, Z1 indicates a bond or a bivalent cyclic ring group, Z2 indicates a bond or a bivalent cyclic ring group, in which the number of atoms constituting the straight-chain portion is 1 to 4, and R2 indicates (1) an amino group that may be substituted, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxide, (2) a nitrogen-containing, heterocyclic ring group that may be substituted and may contain the sulfur atom or the oxygen atom as a ring-constituting atom, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxide, (3) a group that bonded via the sulfur atom, (4) a group represented by formula 
xe2x80x83(wherein k indicates 0 or 1, the phosphorus atom may form a phosphonium salt when k is 0, and each of R5xe2x80x2 and R6xe2x80x2 indicates the hydrocarbon atom that may be substituted, the hydroxyl group that may be substituted or an amino group that may be substituted and R5xe2x80x2 and R6xe2x80x2 may bind each other to form a cyclic ring group together with the adjacent phosphorus atom), (5) an amidino group that may be substituted or (6) a guanidino group that may be substituted] [provided that, when a group represented by formula R1xe2x80x94X1xe2x80x94Wxe2x80x94X2xe2x80x94Z1xe2x80x94Z2xe2x80x94 indicates a group represented by formula 
xe2x80x83(wherein R1 indicates the same meaning as described above, Wxe2x80x2 indicates a bivalent group represented by formula 
xe2x80x83(wherein ring Axe2x80x2 indicates a 5- to 6-membered aromatic ring that may be substituted, X indicates the carbon atom that may be substituted, the nitrogen atom that may be substituted, the sulfur atom or the oxygen atom and ring Bxe2x80x2 indicates a 5- to 7-membered ring that may be substituted) and Z indicates a bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4), R2 indicates an amidino group that may be substituted or a guanidino group that may be substituted], or salts thereof, together with a protease inhibitor and/or a reverse transcriptase inhibitor for preventing and/or treating HIV infectious diseases;
(36) A method for antagonizing CCR (preferably, a method for antagonizing CCR5), which comprises administrating an effective dose of the compound or a salt thereof as described in the above-mentioned item (28) to the mammals;
(37) Use of the compound or a salt thereof as described in the above-mentioned item (28) for manufacturing a medicine for the CCR antagonism (preferably, the CCRS antagonism); and the like.
xe2x80x9cA 5- to 6-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 6-membered cyclic ring group that may be substitutedxe2x80x9d, which is indicated by R1 in the above-mentioned formula (I), is exemplified by a group that is formed by removing one hydrogen atom from a 6-membered aromatic hydrocarbon such as benzene or the like, a 5- to 6-membered aliphatic hydrocarbon such as cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene or the like, a 5- to 6-membered, aromatic heterocyclic ring, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from the nitrogen atom, the sulfur atom and the oxygen atom, such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole or the like, a 5- to 6-membered, non-aromatic heterocyclic ring, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from the nitrogen atom, the sulfur atom and the oxygen atom, such as tetrahydrofuran, tetrahydrothiophene, dithiolan, oxathiolan, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, tetrahydrothiopyran or the like, or the like, where as for xe2x80x9ca 5- to 6-membered cyclic ringxe2x80x9d is preferably benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran (preferably, a 6-membered cyclic ring) or the like, particularly benzene.
Examples of xe2x80x9ca substituentxe2x80x9d that may be possessed by xe2x80x9ca 5- to 6-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 6-membered cyclic ring group that may be substitutedxe2x80x9d, which is indicated by R1 in the above-mentioned formula (I), to be used include a halogen atom, nitro, cyano, an alkyl that may be substituted, a cycloalkyl that may be substituted, the hydroxyl group that may be substituted, the thiol group that may be substituted (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted), an amino group that may be substituted, an acyl that may be substituted, the carboxyl group that may be substituted, an aromatic group that may be substituted and the like.
A halogen as a substituent of R1 is exemplified by fluorine, chlorine, bromine, iodine or the like, where fluorine and chlorine are particularly preferable.
An alkyl for an alkyl that may be substituted as a substituent of R1 is exemplified by a straight-chain or branched alkyl having a carbon number of 1 to 10, for example, a C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl or the like, preferably a lower (C1-6)alkyl. A substituent in said alkyl that may be substituted is exemplified by a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a C1-4 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), a C1-4 alkoxy-C1-4 alkoxyl that may be halogenated (for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy or the like), formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like) or the like, where the number of the substituents is preferably 1 to 3.
A cycloalkyl for a cycloalkyl that may be substituted as a substituent of R1 is exemplified by, for example, a C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like. A substituent in said cycloalkyl that may be substituted is exemplified by a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a C1-4 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), a C1-4 alkoxy-C1-4 alkoxyl that may be halogenated (for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy or the like), formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like) or the like, where the number of the substituents is preferably 1 to 3.
A substituent for the hydroxyl group that may be substituted as a substituent of R1 is exemplified by a substituent such as (1) an alkyl that may be substituted (for example, a C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl or the like, preferably a lower (C1-6)alkyl, or the like is exemplified);
(2) a cycloalkyl that may be substituted and may contain heteroatoms (for example, a C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like; a saturated, 5- to 6-membered heterocyclic ring group containing 1 to 2 heteroatoms such as tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl or the like (preferably, tetrahydropyranyl or the like); or the like is exemplified);
(3) an alkenyl that may be substituted (for example, an alkenyl that has the carbon number of 2 to 10 such as allyl, crotyl, 2-pentenyl, 3-hexenyl or the like, preferably a lower (C2-6)alkenyl, or the like is exemplified);
(4) a cycloalkenyl that may be substituted (for example, an cycloalkenyl that has the carbon number of 3 to 7 such as 2-cyclopentenyl, 2-cyclohexenyl 2-cyclopentenylmethyl, 2-cyclohexenylmethyl or the like, or the like is exemplified);
(5) an aralkyl that may be substituted (for example, a phenyl-C1-4 alkyl (for example, benzyl, phenethyl or the like) or the like is exemplified);
(6) formyl or an acyl that may be substituted (for example, an alkanoyl that has the carbon number of 2 to 4 (for example, acetyl, propionyl, butyryl, isobutyryl or the like), an alkylsulfonyl that has the carbon number of 1 to 4 (for example, methanesulfonyl, ethanesulfonyl or the like) or the like is exemplified); and
(7) an aryl that may be substituted (for example, phenyl, naphthyl or the like is exemplified),
where examples of the substituents that may be possessed by (1) an alkyl that may be substituted, (2) a cycloalkyl that may be substituted, (3) an alkenyl that may be substituted, (4) a cycloalkenyl that may be substituted, (5) an aralkyl that may be substituted, (6) an acyl that may be substituted and (7) an aryl that may be substituted, which are described above, include a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a C1-4 alkyl that may be halogenated (for example, trifluoromethyl, methyl, ethyl or the like), a C1-6 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like; preferably, a C1-4 alkoxyl that may be halogenated), formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like), a 5- to 6-membered, aromatic heterocyclic ring that may be substituted [for example, an aromatic heterocyclic ring, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from the nitrogen atom, the sulfur atom and the oxygen atom, such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole or the like; the substituent that may be possessed by said heteroaromatic ring is exemplified by a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group, an amino group, the carboxyl group, a C1-4 alkyl that may be halogenated (for example, trifluoromethyl, methyl, ethyl or the like), a C1-6 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like), where the number of the substituents is preferably 1 to 3.], or the like, where the number of the substituents is preferably 1 to 3.
A substituent for the thiol group that may be substituted as a substituent of R1 is exemplified by a substituent similar to xe2x80x9ca substituent for the hydroxyl group that may be substituted as a substituent of R1xe2x80x9d, among which preferable is
(1) an alkyl that may be substituted (for example, a C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl or the like, preferably a lower (C1-6)alkyl, or the like is exemplified);
(2) a cycloalkyl that may be substituted and may contain heteroatoms (for example, a C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like is exemplified);
(3) an aralkyl that may be substituted (for example, a phenyl-C1-4 alkyl (for example, benzyl, phenethyl or the like) or the like is exemplified); and
(4) an aryl that may be substituted (for example, phenyl, naphthyl or the like is exemplified),
where examples of the substituents that may be possessed by (1) an alkyl that may be substituted, (2) a cycloalkyl that may be substituted, (3) an aralkyl that may be substituted and (4) an aryl that may be substituted, which are described above, include a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a C1-4 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), a C1-4 alkoxy-C1-4 alkoxyl that may be halogenated (for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy or the like), formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like), where the number of the substituents is preferably 1 to 3.
A substituent for an amino group that may be substituted as a substituent of R1 is exemplified by an amino group that may have 1 to 2 substituents similar to xe2x80x9ca substituent for the hydroxyl group that may be substituted as a substituent of R1xe2x80x9d, among which preferable is (1) an alkyl that may be substituted (for example, a C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl or the like, preferably a lower (C1-6)alkyl, or the like is exemplified);
(2) a cycloalkyl that may be substituted and may contain heteroatoms (for example, a C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like);
(3) an alkenyl that may be substituted (for example, an alkenyl that has the carbon number of 2 to 10 such as allyl, crotyl, 2-pentenyl, 3-hexenyl or the like, preferably a lower (C2-6)alkenyl, or the like is exemplified);
(4) a cycloalkenyl that may be substituted (for example, an cycloalkenyl that has the carbon number of 3 to 7 such as 2-cyclopentenyl, 2-cyclohexenyl 2-cyclopentenylmethyl, 2-cyclohexenylmethyl or the like, or the like is exemplified);
(5) formyl, or an acyl that may be substituted (for example, an alkanoyl that has the carbon number of 2 to 4 (for example, acetyl, propionyl, butyryl, isobutyryl or the like), an alkylsulfonyl that has the carbon number of 1 to 4 (for example, methanesulfonyl, ethanesulfonyl or the like) or the like is exemplified); and
(6) an aryl that may be substituted (for example, phenyl, naphthyl or the like is exemplified),
where examples of the substituents that may be possessed by (1) an alkyl that may be substituted, (2) a cycloalkyl that may be substituted, (3) an alkenyl that may be substituted, (4) a cycloalkenyl that may be substituted, (5) an acyl that may be substituted and (6) an aryl that may be substituted, which are described above, include a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a C1-6 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like), where the number of the substituents is preferably 1 to 3.
Also, as for the substituents for an amino group that may be substituted as a substituent of R1, the substituents for the amino group may bind together to form a cyclic ring amino group (for example, a cyclic ring amino group that is formed by removing one hydrogen from the nitrogen atom constituting the ring of a 5- to 6-membered cyclic ring such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, and has a bond on the nitrogen atom). Said cyclic ring amino group may have substituents, and such substituents are exemplified by a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a C1-6 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), a C1-4 alkoxy-C1-4 alkoxyl that may be halogenated (for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy or the like), formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like), where the number of the substituents is preferably 1 to 3.
An acyl that may be substituted as a substituent of R1 is exemplified by a group, wherein the carbonyl group or the sulfonyl group is bonded with
(1) hydrogen,
(2) an alkyl that may be substituted (for example, a C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl or the like, preferably a lower (C1-6)alkyl, or the like is exemplified);
(3) a cycloalkyl that may be substituted and may contain heteroatoms (for example, a C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like);
(4) an alkenyl that may be substituted (for example, an alkenyl that has the carbon number of 2 to 10 such as allyl, crotyl, 2-pentenyl, 3-hexenyl or the like, preferably a lower (C2-6)alkenyl, or the like is exemplified);
(5) a cycloalkenyl that may be substituted (for example, a cycloalkenyl that has the carbon number of 3 to 7 such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl or the like, or the like is exemplified); or
(6) a 5- to 6-membered, monocyclic ring aromatic group (for example, phenyl, pyridyl or the like is exemplified) that is bonded with the carbonyl group or the sulfonyl group, (for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, methanesulfonyl, ethanesulfonyl or the like), where examples of the substituents that may be possessed by (2) an alkyl that may be substituted, (3) a cycloalkyl that may be substituted, (4) an alkenyl that may be substituted, (5) a cycloalkenyl that may be substituted and (6) a 5- to 6-membered, monocyclic ring aromatic group that may be substituted, which are described above, include a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a C1-6 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), a C1-4 alkoxy-C1-4 alkoxyl that may be halogenated (for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy or the like), formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or t he like), where the number of the substituents is preferably 1 to 3.
The carbonyl group that may be esterified as a substituent of R1 is exemplified by a group, wherein the carbonyloxy group is bonded with
(1) hydrogen,
(2) an alkyl that may be substituted (for example, a C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl or the like, preferably a lower (C1-6)alkyl, or the like is exemplified);
(3) a cycloalkyl that may be substituted and may contain heteroatoms (for example, a C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like);
(4) an alkenyl that may be substituted (for example, an alkenyl that has the carbon number of 2 to 10 such as allyl, crotyl, 2-pentenyl, 3-hexenyl or the like, preferably a lower (C2-6)alkenyl, or the like is exemplified);
(5) a cycloalkenyl that may be substituted (for example, a cycloalkenyl that has the carbon number of 3 to 7 such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl or the like, or the like is exemplified); or
(6) an aryl that may be substituted (for example, phenyl, naphthyl or the like is exemplified), preferably carboxyl, a lower (C1-6)alkoxycarbonyl and an aryloxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl or the like), where examples of the substituents that may be possessed by (2) an alkyl that may be substituted, (3) a cycloalkyl that may be substituted, (4) an alkenyl that may be substituted, (5) a cycloalkenyl that may be substituted and (6) an aryl that may be substituted, which are described above, include a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a C1-6 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), a C1-4 alkoxy-C1-4 alkoxyl that may be halogenated (for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy or the like), formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like), where the number of the substituents is preferably 1 to 3.
The aromatic group for an aromatic group that may be substituted as a substituent of R1 is exemplified by a 5- to 6-membered, same element or heterocyclic ring, aromatic group such as phenyl, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isooxazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl or the like, a condensed, heterocyclic ring aromatic group such as benzofuran, indole, benzothiophene, benzoxazole, benzthiazole, indazole, benzimidazole, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline or the like, or the like. Examples of the substituents for these aromatic groups include a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4alkoxycarbonyl, carbamoyl, a mono-C1-4alkylcarbamoyl, a di-C1-4alkylcarbamoyl or the like), a C1-4alkyl that may be halogenated (for example, trifluoromethyl, methyl, ethyl or the like), a C1-6alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), formyl, a C2-4alkanoyl (for example, acetyl, propionyl or the like), a C1-4alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like), where the number of the substituents is preferably 1 to 3.
Such a substituent of R1 may be substituted at any position of 1 to 4 (preferably, 1 to 2) of the same or different cyclic rings. Also, in the case where xe2x80x9ca 5- to 6-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 6-membered cyclic ring that may be substitutedxe2x80x9d, which is indicated by R1, has 2 or more substituents, 2 substituents of them may be bonded together to form, for example, a lower (C1-6)alkylene (for example, trimethylene, tetramethylene or the like), a lower (C1-6)alkyleneoxy (for example, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94C(CH3) (CH3)xe2x80x94CH2xe2x80x94CH2xe2x80x94 or the like), a lower (C1-6)alkylenethio (for example, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94C(CH3)(CH3)xe2x80x94CH2xe2x80x94CH2xe2x80x94 or the like), a lower (C1-6)alkylenedioxy (for example, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94 or the like), a lower (C1-6)alkylenedithio (for example, xe2x80x94Sxe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94 or the like), an oxy-lower (C1-6)alkylenamino (for example, xe2x80x94Oxe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94 or the like), an oxy-lower (C1-6)alkylenethio (for example, xe2x80x94Oxe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94 or the like), a lower (C1-6)alkylenamino (for example, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 or the like), a lower (C1-6)alkylenediamino (for example, xe2x80x94NHxe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94 or the like), a thia-lower (C1-6)alkylenamino (for example, xe2x80x94Sxe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94 or the like), a lower (C2-6)alkenylene (for example, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94 or the like), a lower (C4-6)alkadienylene (for example, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or the like) or the like.
Furthermore, the bivalent group that is formed by binding each other 2 substituents of R1 may have 1 to 3 substituents similar to xe2x80x9cthe substituentxe2x80x9d that may be possessed by xe2x80x9ca 5- to 6-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 6-membered cyclic ring that may be substitutedxe2x80x9d, which is indicated by R1, (a halogen atom, nitro, cyano, an alkyl that may be substituted, a cycloalkyl that may be substituted, the hydroxyl group that may be substituted, the thiol group that may be substituted (the sulfur atom may be oxidized to form a sulfinyl group that may be substituted or a sulfonyl group that may be substituted), an amino group that may be substituted, an acyl that may be substituted, the carboxyl group that may be esterified or amidated, an aromatic group that may be substituted and the like).
xe2x80x9cThe substituentxe2x80x9d that may be possessed by xe2x80x9ca 5- to 6-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 6-membered cyclic ring that may be substitutedxe2x80x9d, which is indicated by R1, is exemplified particularly by a lower (C1-4)alkyl that may be halogenated or alkoxylated with a lower (C1-4) (for example, methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, or the like), a lower (C1-4)alkoxyl that may be halogenated or alkoxylated with a lower (C1-4) (for example, methoxy, ethoxy, propoxy, butoxy, t-butoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxymethoxy, propoxyethoxy, butoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy or the like), a halogen (for example, fluorine, chlorine or the like), nitro, cyano, an amino group that may be substituted with 1 to 2 of a lower (C1-4)alkyl, formyl or a lower (C1-4)alkanoyl (for example, amino, methylamino, dimethylamino, formylamino, acetylamino or the like), a 5- to 6-membered cyclic ring amino group (for example, 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, 4-morpholino, 4-thiomorpholino, 1-imidazolyl, 4-tetrahydropyranyl or the like) or the like.
xe2x80x9cA bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4xe2x80x9d, indicated by X1 and X2, is exemplified by, for example, xe2x80x94(CH2)axe2x80x2xe2x80x94 [axe2x80x2 indicates an integer of 1 to 4 (preferably, an integer of 1 to 2)], xe2x80x94(CH2)bxe2x80x2xe2x80x94X3xe2x80x94 [bxe2x80x2 indicates an integer of 0 to 3 (preferably, an integer of 0 to 1) and X3 indicates an imino group that may be substituted (for example, an imino group that may be substituted with a lower (C1-6)lower alkyl, a lower (C3-7)cycloalkyl, formyl, a lower (C2-7) lower alkanoyl, a lower (C1-6)lower alkoxycarbonyl or the like), the carbonyl group, the oxygen atom, the sulfur atom that may be oxidized by the oxygen atom (for example, xe2x80x94S(O)mxe2x80x94 (m indicates an integer of 0 to 2) or the like)], xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94SO2xe2x80x94NHxe2x80x94 or the like. Although these groups may be bonded with W through either of the left or right bond, it is preferable to be bonded with W through the right hand in the case of X1, whereas it is preferable to be bonded with W through the left hand in the case of X2.
As for X1, a bond, xe2x80x94(CH2)bxe2x80x2xe2x80x94Oxe2x80x94 [bxe2x80x2 indicates an integer of 0, 1 or 2 (preferably, an integer of 0 to 1), xe2x80x94Cxe2x89xa1Cxe2x80x94 or the like is preferable, and a bond is more preferable.
As for X2, xe2x80x94(CH2)axe2x80x2xe2x80x94 [axe2x80x2 indicates an integer of 1 to 2], xe2x80x94(CH2)bxe2x80x2xe2x80x94X3xe2x80x94 [bxe2x80x2 indicates an integer of 0 to 1 and X3 indicates an imino group that may be substituted, the carbonyl group, the oxygen atom, the sulfur atom that may be oxidized by the oxygen atom], xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94SO2xe2x80x94NHxe2x80x94 or the like is preferable, and xe2x80x94COxe2x80x94NHxe2x80x94 is more preferable.
In the above-mentioned formula (I), a bivalent group that is represented by formula indicated by W 
(wherein each of ring A and ring B indicates a 5- to 7-membered cyclic ring group that may be substituted, each of E1 and E4 indicates the carbon atom that may be substituted or the nitrogen atom that may be substituted, each of E2 and E3 indicates the carbon atom that may be substituted or the nitrogen atom that may be substituted, the sulfur atom that may be oxidized (for example, xe2x80x94S(O)mxe2x80x94 (m indicates an integer of 0 to 2) or the like) or the oxygen atom and each of a and b indicates to be a single bond or a double bond) indicates that the bonding with adjacent X1 and X2 is made in a mode that is shown respectively by 
(wherein each of the symbols has the same meaning as that described hereinabove).
In the above-mentioned formula (I), xe2x80x9ca 5- to 7-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 7-membered cyclic ring that may be substitutedxe2x80x9d, which is indicated by A, is exemplified by a 5- to 7-membered (preferably, 5- to 6-membered, saturated or unsaturated alicyclic hydrocarbon such as a C5-7 cycloalkane (for example, cyclopentane, cyclohexane, cycloheptane or the like), a C5-7 cycloalkene (for example, 1-cyclopentene, 2-cyclopentene, 3-cyclopentene, 2-cyclohexene, 3-cyclohexene or the like), a C5-6 cycloalkadiene (for example, 2,4-cyclopentadiene, 2,4-cyclohexadiene, 2,5-cyclohexadiene or the like); a 6-membered aromatic hydrocarbon such as benzene; a 5- to 7-membered, aromatic heterocyclic ring, a saturated or unsaturated non-aromatic heterocyclic ring (aliphatic heterocyclic ring) or the like, which contains at least one (preferably, 1 to 4, more preferably 1 to 2) of heteroatoms of 1 to 3 kinds (preferably, 1 to 2 kinds) selected from the oxygen atom, the sulfur atom and the nitrogen atom; or the like.
Herein, xe2x80x9can aromatic heterocyclic ringxe2x80x9d is exemplified by a 5- to 7-membered, aromatic monocyclic, heterocyclic ring (for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine or the like) or the like, and xe2x80x9ca non-aromatic heterocyclic ringxe2x80x9d is exemplified by, for example, a 5- to 7-membered (preferably, 5- to 6-membered), saturated or unsaturated non-aromatic heterocyclic ring (aliphatic heterocyclic ring) such as pyrrolidine, tetrahydrofuran, thiolane, piperidine, tetrahydropyran, morpholine, thiomorpholine, piperazine, pyran, oxepine, azepine or the like, a 5- to 6-membered, non-aromatic heterocyclic ring, where a part or all of the double bonds in the above-mentioned aromatic monocyclic heterocyclic ring are saturated, or the like.
As for xe2x80x9ca 5- to 7-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 7-membered cyclic ring that may be substitutedxe2x80x9d, which is indicated by A, a 5- to 6-membered, aromatic ring is preferable, and further benzene, furan, thiophene, pyrrole, pyridine (preferably, 6-membered) or the like is preferable, where benzene is particularly preferable.
xe2x80x9cThe substituentxe2x80x9d that may be possessed by xe2x80x9ca 5- to 7-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 7-membered cyclic ring that may be substitutedxe2x80x9d, which is indicated by A, is exemplified by a group similar to xe2x80x9cthe substituentxe2x80x9d that may be possessed by xe2x80x9ca 5- to 6-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 6-membered cyclic ring that may be substitutedxe2x80x9d, which is indicated by R1. Also, such a substituent for A may be substituted at any positions of 1 to 4 (preferably, 1 to 2) of the same or different rings, and the substituent may be possessed at any substitutable position, whether it is any of the positions that are indicated by E1 and E2 or any of other positions.
In the above-mentioned formula (I), xe2x80x9ca 5- to 7-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 7-membered cyclic ring that may be substitutedxe2x80x9d, which is indicated by B, is exemplified by a 5- to 7-membered cyclic ring that may have substituents at optional, substitutable positions, which is represented by formula 
or the like.
In the above-mentioned formula (I), the bivalent group that is indicated by Y indicates a bivalent group, with which ring B forms a 5- to 7-membered cyclic ring that may be substituted, and is exemplified by a bivalent group such as, for example,
(1) xe2x80x94(CH2)a1xe2x80x94Oxe2x80x94(CH2)a2xe2x80x94 (each of a1 and a2 indicates 0, 1 or 2 in the same or different manner. Hereupon, the sum of a1 and a2 is 2 or less), xe2x80x94Oxe2x80x94(CHxe2x95x90CH)xe2x80x94, xe2x80x94(CHxe2x95x90CH)xe2x80x94Oxe2x80x94,
(2) xe2x80x94(CH2)b1xe2x80x94S(O)mxe2x80x94(CH2)b2xe2x80x94 (m indicates an integer of 0 to 2, and each of b1 and b2 indicates 0, 1 or 2 in the same or different manner. Hereupon, the sum of b1 and b2 is 2 or less), xe2x80x94S(O)mxe2x80x94(CHxe2x95x90CH)xe2x80x94, xe2x80x94(CHxe2x95x90CH)xe2x80x94S(O)mxe2x80x94,
(3) xe2x80x94(CH2)d1xe2x80x94 (d1 indicates 0, 1 or 2), xe2x80x94CH2xe2x80x94(CHxe2x95x90CH)xe2x80x94, xe2x80x94(CHxe2x95x90CH)xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90,
(4) xe2x80x94(CH2)e1xe2x80x94NHxe2x80x94(CH2)e2xe2x80x94 (each of e1 and e2 indicates 0, 1 or 2 in the same or different manner. Hereupon, the sum of e1 and e2 is 2 or less), xe2x80x94NHxe2x80x94(CHxe2x95x90CH)xe2x80x94, xe2x80x94(CHxe2x95x90CH)xe2x80x94NHxe2x80x94, xe2x80x94(CH2)e6xe2x80x94(Nxe2x95x90CH)xe2x80x94(CH2)e7xe2x80x94, xe2x80x94(CH2)e7xe2x80x94(CHxe2x95x90N)xe2x80x94(CH2)e6xe2x80x94 (either of e6 and e7 indicates 0, and the other indicates 0 or 1), xe2x80x94(CH2)e8xe2x80x94(Nxe2x95x90N)xe2x80x94(CH2)e9xe2x80x94 (either of e8 and e9 indicates 0, and the other indicates 0 or 1) or the like. Specifically, the bivalent group is exemplified by, for example, a bivalent group such as xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94(CHxe2x95x90CH)xe2x80x94, xe2x80x94S(O)mxe2x80x94 (m indicates an integer of 0 to 2), xe2x80x94S(O)mxe2x80x94CH2xe2x80x94 (m indicates an integer of 0 to 2), xe2x80x94S(O)mxe2x80x94CH2xe2x80x94CH2xe2x80x94 (m indicates an integer of 0 to 2), xe2x80x94S(O)mxe2x80x94(CHxe2x95x90CH)xe2x80x94, (m indicates an integer of 0 to 2), xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CHxe2x95x90, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94 (respectively, the bonding indicated starts from ring A) or the like.
In addition, said bivalent group may have a substituent, and said substituent is exemplified by a group similar to xe2x80x9cthe substituentxe2x80x9d that may be possessed by xe2x80x9ca 5- to 6-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 6-membered cyclic ring that may be substitutedxe2x80x9d, which is indicated by R1, oxo and the like, where a lower (C1-3)alkyl (for example, methyl, ethyl, propyl or the like), phenyl, oxo, the hydroxyl group or the like is particularly preferable. Furthermore, said bivalent group may be xe2x80x94Oxe2x80x94C(O)xe2x80x94 (the bonding indicated starts from ring A) or the like. The substituent for such a bivalent group may be substituted at any same or different positions of 1 to 4 (preferably, 1 to 2). The substituent position may be any position that is substitutable to said bivalent group.
As for the bivalent group that is indicated by Y, a group such as xe2x80x94Yxe2x80x2xe2x80x94(CH2)mxe2x80x2xe2x80x94 (Yxe2x80x2 indicates xe2x80x94S(O)mxe2x80x94 (m indicates an integer of 0 to 2), xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94, and mxe2x80x2 indicates an integer of 0 to 2), xe2x80x94CHxe2x95x90, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94(CH2)mxe2x80x2xe2x80x94Yxe2x80x2xe2x80x94 (Yxe2x80x2 indicates xe2x80x94S(O)mxe2x80x94 (m indicates an integer of 0 to 2), xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94, and mxe2x80x2 indicates an integer of 0 to 2), xe2x80x94CHxe2x95x90Nxe2x80x94 or the like, with starting the bonding indicated from ring A, is preferable, where a group such as xe2x80x94Yxe2x80x2xe2x80x94(CH2)mxe2x80x2xe2x80x94 (Yxe2x80x2 indicates xe2x80x94S(O)mxe2x80x94 (m indicates an integer of 0 to 2), xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94, and mxe2x80x2 indicates an integer of 0 to 2), xe2x80x94CHxe2x95x90, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94 or the like, with starting the bonding indicated from ring A, is more preferable, and a group (ring B indicates a 7-membered ring) such as xe2x80x94Yxe2x80x2xe2x80x94(CH2)2xe2x80x94 (Yxe2x80x2 indicates xe2x80x94S(O)mxe2x80x94 (m indicates an integer of 0 to 2), xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94), with starting the bonding indicated from ring A, is most preferable.
xe2x80x9cThe substituentxe2x80x9d that may be possessed by xe2x80x9ca 5- to 7-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 7-membered cyclic ring that may be substitutedxe2x80x9d, which is indicated by B, is exemplified by a group similar to xe2x80x9cthe substituentxe2x80x9d that may be possessed by xe2x80x9ca 5- to 6-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 6-membered cyclic ring that may be substitutedxe2x80x9d, which is indicated by R1. Also, such a substituent for B may be substituted at any positions of 1 to 4 (preferably, 1 to 2) of the same or different rings, but it is preferable that the position of E3 is unsubstituted.
In the above-mentioned formula (I), it is preferable that each of E3 and E4 is the carbon atom that may be substituted (preferably, the carbon atom that is not substituted), and b indicates a double bond.
In the above-mentioned formula (I), xe2x80x9ca bivalent cyclic ring groupxe2x80x9d indicated by Z1 is exemplified by a group that is formed by removing two hydrogen atoms from a group similar to xe2x80x9ca 5- to 6-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 6-membered cyclic ring that may be substitutedxe2x80x9d, or the like, where a bivalent cyclic ring group, which is formed by removing two hydrogen atoms from benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or tetrahydropyran, is more preferable, and a bivalent cyclic ring group, which is formed by removing two hydrogen atoms from benzene, cyclohexane or piperidine (preferably, benzene) is most preferably used.
xe2x80x9cA bivalent cyclic ring groupxe2x80x9d indicated by Z1 may have a substituent similar to xe2x80x9ca substituentxe2x80x9d that is possessed by xe2x80x9ca 5- to 6-membered cyclic ringxe2x80x9d of xe2x80x9ca 5- to 6-membered cyclic ring that may be substitutedxe2x80x9d, but it is preferable not to have a substituent other than X2 and Z2, and also it is preferable that the substitution position for Z2 is para to X2 in the case where Z1 is a 6-membered, bivalent cyclic ring group (preferably, phenylene).
In the above-mentioned formula (I), xe2x80x9ca bivalent group, in which the number of atoms constituting the straight-chain portion is 1 to 4xe2x80x9d, which is indicated by Z2, is exemplified by a bivalent group that has a hydrocarbon chain having the carbon number of 1 to 4, which may be substituted (for example, a C1-4 alkylene, a C2-4 alkenylene or the like, preferably a C1-3 alkylene, more preferably methylene), or the like.
A bivalent group, which is indicated by Z2, may be any group having a bivalent chain, in which the number of atoms constituting the straight-chain portion is 1 to 4, and is exemplified by, for example, an alkylene chain represented by xe2x80x94(CH2)k1xe2x80x94(k1 is an integer of 1 to 4), an alkenylene chain represented by xe2x80x94(CH2)k2xe2x80x94(CHxe2x95x90CH)xe2x80x94(CH2)k3xe2x80x94 (each of k2 and k3 indicates an integer of 1 to 4 in the same or different manner. Hereupon, the sum of k2 and k3 is 2 or less) or the like.
A bivalent group, which is indicated by X1, X2 and Z2, may have a substituent at an optional position (preferably, on the carbon atom), where such a substituent may be any one that is capable of being bonded to a bivalent chain constituting the straight-chain portion, is exemplified by, for example, a lower (C1-6)alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl or the like), a lower (C3-7)cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like), formyl, a lower (C2-7)alkanoyl (for example, acetyl, propionyl, butyryl or the like), a phosphono group that may be esterified, the carboxyl group that may be esterified, the hydroxyl group, oxo or the like, where preferably a lower alkyl having the carbon number of 1 to 6 (preferably a C1-3 alkyl), the hydroxyl group, oxo or the like is exemplified.
Said phosphono group that may be esterified is exemplified by a group represented by xe2x80x94P(O) (OR7) (OR8) [wherein each of R7 and R8 indicates hydrogen, an alkyl group having the carbon number of 1 to 6 or a cycloalkyl group having the carbon number of 3 to 7, and may be bonded together to form a 5- to 7-membered cyclic ring].
In the above-mentioned formula, an alkyl group having the carbon number of 1 to 6, which is represented by R7 and R8, is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl or the like, and a cycloalkyl having the carbon number of 3 to 7 is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like), where a lower alkyl having the carbon number of 1 to 6 is exemplified preferably, and a lower alkyl having the carbon number of 1 to 3 is exemplified more preferably. R7 and R8 may be the same or different, but it is preferable to be the same. Also, in the case where R7 and R8 are bonded together to form a 5- to 7-membered cyclic ring, R7 and R8 are bonded together to form a straight-chained C2-4 alkylene side chain represented by xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94. Said side chain may have substituents, and such a substituent is exemplified by, for example, the hydroxyl group, a halogen or the like.
The carboxyl group, which is esterified for the carboxyl group that may be esterified, is exemplified by a group, wherein the carboxyl group is bonded with an alkyl group having the carbon number of 1 to 6 or a cycloalkyl having the carbon number of 3 to 7, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl or the like.
A bivalent group, which is indicated by Z2, is exemplified by a C1-3 alkylene that may be substituted, where a C1-3 alkylene that may be substituted with a C1-3 alkyl, the hydroxyl group or oxo is more preferable.
Furthermore, as for a bivalent group, which is indicated by Z2, a group represented by xe2x80x94Zxe2x80x2xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94Zxe2x80x2xe2x80x94 (Zxe2x80x2 indicates xe2x80x94CH(OH)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94, n indicates an integer of 0 to 2 and each methylene group may have 1 to 2 groups of the same or different substituent), with starting from the benzene ring, is preferable, a group represented by xe2x80x94Zxe2x80x2xe2x80x94(CH2)nxe2x80x94 (Zxe2x80x2 indicates xe2x80x94CH(OH)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94, n indicates an integer of 0 to 2 (preferably, n indicates 0) and each methylene group may have 1 to 2 groups of the same or different substituents), with starting from the benzene ring, is more preferable and methylene is most preferable.
In the above-mentioned formula (I), xe2x80x9can amino groupxe2x80x9d of xe2x80x9can amino group that may be substituted, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxidexe2x80x9d indicated by R2, is exemplified by an amino group that may have 1 to 2 substituents, an amino group that has 4 substituents, where the nitrogen atom may be converted into a quaternary ammonium, or the like. In the case where the substituents on the nitrogen atom are 2 or more, these substituents may be the same or different, and in the case where the substituents on the nitrogen atom are 3, the amino group may be of any type of xe2x80x94N+R3, xe2x80x94N+R2Rxe2x80x2, xe2x80x94N+RRxe2x80x2Rxe2x80x3 (each of R, Rxe2x80x2 and Rxe2x80x3 indicates hydrogen or a substituent in a different manner). In addition, a counter anion for the amino group, in which the nitrogen atom is converted into a quaternary ammonium, is exemplified by, in addition to an anion of a halogen atom (for example, Clxe2x88x92, Brxe2x88x92, Ixe2x88x92 or the like) or the like, an anion derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, an anion derived from an organic acid such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like and an anion derived from an acidic amino acid such as aspartic acid, glutamic acid and the like, where Clxe2x88x92, Brxe2x88x92, Ixe2x88x92 or the like is more preferable.
Examples of substituents for said amino group include substituents such as,
(1) an alkyl that may be substituted (for example, a C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl or the like, preferably a lower (C1-6)alkyl or the like is exemplified);
(2) a cycloalkyl that may be substituted and may contain heteroatoms (for example, a C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like is exemplified);
(2-1) said cycloalkyl contains one heteroatom selected from the sulfur atom, the oxygen atom and the nitrogen atom, and may form oxirane, thiolane, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran 1-oxide, piperidine or the like (preferably, a 6-membred ring such as tetrahydropyran, tetrahydrothiopyran, piperidine or the like), where the binding position with the amino group is preferably position 3 or position 4 (preferably, position 4);
(2-2) also, said cycloalkyl may condensed with the benzene ring to form an indane (for example, indan-2-yl, indan-2-yl or the like), tetrahydronaphthalene, (for example, tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl or the like) or the like (preferably, indane);
(2-3) furthermore, said cycloalkyl may be crosslinked via a straight-chained, atom chain having the carbon number of 1 to 2 to form a crosslinked, cyclic hydrocarbon residue such as bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl or the like (preferably, a cycloalkyl having a crosslink via a straight-chained, atom chain having the carbon number of 1 to 2, or the like, more preferably bicyclo[2.2.1]heptyl or the like);
(3) an alkenyl that may be substituted (for example, an alkenyl that has the carbon number of 2 to 10 such as allyl, crotyl, 2-pentenyl, 3-hexenyl or the like, preferably a lower (C2-6)alkenyl, or the like is exemplified);
(4) a cycloalkenyl that may be substituted (for example, an cycloalkenyl that has the carbon number of 3 to 7 such as 2-cyclopentenyl, 2-cyclohexenyl 2-cyclopentenylmethyl, 2-cyclohexenylmethyl or the like, or the like is exemplified);
(5) an aralkyl that may be substituted (for example, a phenyl-C1-4 alkyl (for example, benzyl, phenethyl or the like) or the like is exemplified);
(6) formyl or an acyl that may be substituted (for example, an alkanoyl that has the carbon number of 2 to 4 (for example, acetyl, propionyl, butyryl, isobutyryl or the like), an alkylsulfonyl that has the carbon number of 1 to 4 (for example, methanesulfonyl, ethanesulfonyl or the like), an alkoxycarbonyl that has the carbon number of 1 to 4 (methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or the like), an aralkyloxycarbonyl that has the carbon number of 7 to 10 (for example, benzyloxycarbonyl or the like) or the like is exemplified);
(7) an aryl that may be substituted (for example, phenyl, naphthyl or the like is exemplified); and
(8) a heterocyclic ring group that may be substituted (a group that is formed by removing one hydrogen atom from a 5- to 6-membered, aromatic heterocyclic ring, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from the nitrogen atom, the sulfur atom and the oxygen atom, such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole or the like, a group that is formed by removing one hydrogen atom from a 5- to 6-membered, non-aromatic heterocyclic ring, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from the nitrogen atom, the sulfur atom and the oxygen atom, such as tetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran or the like, or the like; preferably, a group, which is formed by removing one hydrogen atom from a 5- to 6-membered, non-aromatic heterocyclic ring, or the like; and more preferably, a group, which is formed by removing one hydrogen atom from a 5- to 6-membered, non-aromatic heterocyclic ring, which has one heteroatom, such as tetrahydrofuran, piperidine, tetrahydropyran, tetrahydrothiopyran or the like) and the like. In addition, the substituents of said amino group may be bonded each other to form a 5- to 7-membered, cyclic amino such as piperidine, piperazine, morpholine, thiomorpholine or the like.
Examples of the substituents that may be possessed by (1) an alkyl that may be substituted, (2) a cycloalkyl that may be substituted, (3) an alkenyl that may be substituted, (4) a cycloalkenyl that may be substituted, (5) an aralkyl that may be substituted, (6) an acyl that may be substituted, (7) an aryl that may be substituted and (8) a heterocyclic ring group that may be substituted, which are described above, include a halogen (for example, fluorine, chlorine, bromine, iodine or the like), a lower (C1-4)alkyl that may be halogenated, a C1-4 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), a C1-4 alkylenedioxy (for example, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94 or the like), formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like), a phenyl-lower (C1-4)alkyl, a C3-7 cycloalkyl, cyano, nitro, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a lower (C1-4) alkoxycarbonyl, a lower (C7-10)aralkyloxycarbonyl, the oxo group (preferably, a halogen, a lower (C1-4)alkyl that may be halogenated, a C1-4 alkoxyl that may be halogenated, a phenyl-lower (C1-4)alkyl, a C3-7 cycloalkyl, cyano, the hydroxyl group or the like) and the like, where the number of the substituents is preferably 1 to 3.
In the above-mentioned formula (I), xe2x80x9can amino group that may be substituted, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxidexe2x80x9d indicated by R2, is preferably an amino group that may have 1 to 3 substituents selected from,
(1) a straight-chained or branched, lower (C1-6)alkyl that may have 1 to 3 groups of a halogen, cyano, the hydroxyl group or a C3-7 cycloalkyl;
(2) a C5-8 cycloalkyl that may have 1 to 3 groups of a halogen, a lower (C1-4)alkyl that may be halogenated or a phenyl-lower (C1-4)alkyl, may contain one heteroatom selected from the sulfur atom, the oxygen atom and the nitrogen atom, may be condensed with the benzene ring and may be crosslinked via a straight-chained, atom chain having the carbon number of 1 to 2, (for example, cyclopentyl, cyclohexyl, cycloheptyl cyclooctyl, tetrahydropyranyl, tetrahydrothiapyranyl, piperidinyl, indanyl, tetrahydronaphthalenyl, bicyclo[2.2.1]heptyl or the like);
(3) a phenyl-lower (C1-4)alkyl that may have 1 to 3 groups of a halogen, a lower (C1-4)alkyl that may be halogenated or a C1-4 alkoxyl that may be halogenated;
(4) a phenyl that may have 1 to 3 groups of a halogen, a lower (C1-4)alkyl that may be halogenated or a C1-4 alkoxyl that may be halogenated; and
(5) a 5- to 6-membered, aromatic heterocyclic ring that may have 1 to 3 groups of a halogen, a lower (C1-4)alkyl that may be halogenated, a C1-4 alkoxyl that may be halogenated, a (C1-4)alkoxy-(C1-4)alkoxyl that may be halogenated, a phenyl-lower (C1-4)alkyl, cyano or the hydroxyl (for example, a group that is formed by removing one hydrogen atom from furan, thiophene, pyrrole, pyridine or the like).
In the above-mentioned formula (I), xe2x80x9ca nitrogen-containing, heterocyclic ringxe2x80x9d of xe2x80x9ca nitrogen-containing, heterocyclic ring group that may be substituted and may contain the sulfur atom or the oxygen atom as a ring-constituting atom, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxidexe2x80x9d is exemplified by a 5- to 6-membered, aromatic heterocyclic ring, which may contain, in addition to one nitrogen atom, 1 to 3 heteroatoms of 1 to 2 kinds selected from the nitrogen atom, the sulfur atom and the oxygen atom, such as pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole or the like, a 5- to 8-membered, non-aromatic heterocyclic ring, which may contain, in addition to one nitrogen atom, 1 to 3 heteroatoms of 1 to 2 kinds selected from the nitrogen atom, the sulfur atom and the oxygen atom, such as pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, azacycloheptane, azacyclooctane (azokane) or the like, or the like, where each of these nitrogen-containing, heterocyclic rings may be crosslinked via a straight-chained, atom chain having the carbon number of 1 to 2 and may form a crosslinked, nitrogen-containing, heterocyclic ring such as azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane (quinuclidine) or the like (preferably, piperidine, which may have a crosslink via a straight-chained, atom chain having the carbon number of 1 to 2, or the like).
Among the specific examples of the above-mentioned, nitrogen-containing, heterocyclic ring, pyridine, imidazole, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and azabicyclo[2.2.2]octane (preferably, 6-membered, cyclic rings) are preferable.
The nitrogen atom of said xe2x80x9cnitrogen-containing, heterocyclic ringxe2x80x9d may be converted into a quaternary ammonium, or may be oxidized. In the case where the nitrogen atom of said xe2x80x9cnitrogen-containing, heterocyclic ringxe2x80x9d is converted into a quaternary ammonium, a counter anion for xe2x80x9cthe nitrogen-containing, heterocyclic ring group, in which the nitrogen atom is converted into a quaternary ammoniumxe2x80x9d, is exemplified by, in addition to an anion of a halogen atom (for example, Clxe2x88x92, Brxe2x88x92, Ixe2x88x92 or the like) or the like, an anion derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, an anion derived from an organic acid such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like and an anion derived from an acidic amino acid such as aspartic acid, glutamic acid and the like, where Clxe2x88x92, Brxe2x88x92, Ixe2x88x92 or the like is more preferable.
Said xe2x80x9cnitrogen-containing, heterocyclic ringxe2x80x9d may be bonded with a bivalent group, which is indicated by Z2, via either of the carbon atom or the nitrogen atom and may be bonded on the carbon atom constituting the cyclic ring, as in the case of 2-pyridyl, 3-pyridyl, 2-piperidyl or the like, whereas a bonding as in the case of 
or the like is preferable.
Examples of substituents of said xe2x80x9cnitrogen-containing, heterocyclic ringxe2x80x9d include a halogen (for example, fluorine, chlorine, bromine, iodine or the like), a lower (C1-4)alkyl that may be substituted, a lower (C1-4)alkoxyl that may be substituted, a phenyl that may be substituted, a mono- or diphenyl-lower (C1-4)alkyl that may be substituted, a C3-7 cycloalkyl that may be substituted, cyano, nitro, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a lower (C1-4)alkoxycarbonyl, formyl, a (C2-4)alkanoyl, a (C1-4) alkylsulfonyl, a heterocyclic ring group that may be substituted (a group that is formed by removing one hydrogen atom from a 5- to 6-membered, aromatic heterocyclic ring, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from the nitrogen atom, the sulfur atom and the oxygen atom, such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole or the like, a group that is formed by removing one hydrogen atom from a 5- to 6-membered, non-aromatic heterocyclic ring, which contains 1 to 4 heteroatoms of 1 to 2 kinds selected from the nitrogen atom, the sulfur atom and the oxygen atom, such as tetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, tetrahydrothiopyran or the like, or the like, where the number of the substituents is preferably 1 to 3. Also, the nitrogen in said xe2x80x9cnitrogen-containing, heterocyclic ringxe2x80x9d may be oxidized.
Examples of the substituents, which may be possessed by xe2x80x9ca lower (C1-4)alkyl that may be substitutedxe2x80x9d, xe2x80x9ca lower (C1-4)alkoxyl that may be substitutedxe2x80x9d, xe2x80x9ca phenyl that may be substitutedxe2x80x9d, xe2x80x9ca mono- or diphenyl-lower (C1-4) alkyl that may be substitutedxe2x80x9d, xe2x80x9ca C3-7 cycloalkyl that may be substitutedxe2x80x9d and xe2x80x9ca heterocyclic ring group that may be substitutedxe2x80x9d, as the substituents that may be possessed by said xe2x80x9cnitrogen-containing, heterocyclic ringxe2x80x9d, include, for example, a halogen (for example, fluorine, chlorine, bromine, iodine or the like), a lower (C1-4)alkyl that may be halogenated, a lower (C3-10)cycloalkyl, a lower (C3-10) cycloalkenyl, a C1-4 alkoxyl that may be halogenated (for example, methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy or the like), formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like), a C1-3 alkylenedioxy (for example, methylenedioxy, ethylenedioxy or the like), cyano, nitro, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a lower (C1-4)alkoxycarbonyl and the like, where the number of the substituents is preferably 1 to 3.
In the above-mentioned formula (I), the substituent, which may be possessed by xe2x80x9ca nitrogen-containing, heterocyclic ringxe2x80x9d of xe2x80x9ca nitrogen-containing, heterocyclic ring group that may be substituted and may contain the sulfur atom or the oxygen atom as a ring-constituting atom, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxidexe2x80x9d is exemplified preferably by (1) a halogen, (2) cyano, (3) the hydroxyl group, (4) the carboxyl group, (5) a lower (C1-4) alkoxycarbonyl, (6) a lower (C1-4)alkyl that may be substituted with a halogen, the hydroxyl group or a lower (C1-4)alkoxyl, (7) a lower (C1-4)alkoxyl that may be substituted with a halogen, the hydroxyl group or a lower (C1-4)alkoxyl, (8) a phenyl that may be substituted with a halogen, a lower (C1-4)alkyl, the hydroxyl group, a lower (C1-4)alkoxyl or a C1-3 alkylenedioxy, (9) a mono- or diphenyl-lower (C1-4)alkyl that may be substituted with a halogen, a lower (C1-4)alkyl, the hydroxyl group, a lower (C1-4)alkoxyl or a C1-3 alkylenedioxy, (10) a group that is formed by removing one hydrogen atom from a 5- to 6-membered, aromatic heterocyclic ring, such as furan, thiophene, pyrrole, pyridine or the like, or the like.
In the above-mentioned formula (I), xe2x80x9ca group that is bonded via the sulfur atomxe2x80x9d, which is indicated by R2, is exemplified by a group represented by xe2x80x94S(O)mxe2x80x94Rs (wherein m indicates an integer of 0 to 2 and Rs indicates a substituent). In the above-mentioned formula, examples of the substituent indicated by Rs include, for example,
(1) an alkyl that may be substituted (for example, a C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl or the like, preferably a lower (C1-6)alkyl, or the like is exemplified);
(2) a cycloalkyl that may be substituted and may contain heteroatoms (for example, a C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like is exemplified);
(3) an aralkyl that may be substituted (for example, a phenyl-C1-4 alkyl (for example, benzyl, phenethyl or the like) or the like is exemplified); and
(4) an aryl that may be substituted (for example, phenyl, naphthyl or the like is exemplified), where examples of the substituents that may be possessed by (1) an alkyl that may be substituted, (2) a cycloalkyl that may be substituted, (3) an aralkyl that may be substituted and (4) an aryl that may be substituted, which are described above, include a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a C1-4 alkyl that may be halogenated (for example, trifluoromethyl, methyl, ethyl or the like), a C1-4 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like) or the like, where the number of the substituents is preferably 1 to 3.
In the above-mentioned formula (I), xe2x80x9cthe hydrocarbon atomxe2x80x9d for the hydrocarbon atom that may be substituted, which is indicated by R5xe2x80x2 and R6xe2x80x2, in xe2x80x9ca group represented by formula 
(wherein k indicates 0 or 1, the phosphorus atom may form a phosphonium salt when k is 0, and each of R5xe2x80x2 and R6xe2x80x2 indicates the hydrocarbon atom that may be substituted, the hydroxyl group that may be substituted or an amino group that may be substituted (preferably, the hydrocarbon atom that may be substituted or an amino group that may be substituted; more preferably the hydrocarbon atom that may be substituted) and R5xe2x80x2 and R6xe2x80x2 may bind each other to form a cyclic ring group together with the adjacent phosphorus atom)xe2x80x9d, which is indicated by R2, is exemplified by,
(1) an alkyl that may be substituted (for example, a C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl or the like, preferably a lower (C1-6)alkyl, or the like is exemplified);
(2) a cycloalkyl that may be substituted (for example, a C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like);
(3) an alkenyl that may be substituted (for example, an alkenyl that has the carbon number of 2 to 10 such as allyl, crotyl, 2-pentenyl, 3-hexenyl or the like, preferably a lower (C2-6)alkenyl, or the like is exemplified);
(4) a cycloalkenyl that may be substituted (for example, an cycloalkenyl that has the carbon number of 3 to 7 such as 2-cyclopentenyl, 2-cyclohexenyl 2-cyclopentenylmethyl, 2-cyclohexenylmethyl or the like, or the like is exemplified);
(5) an alkynyl that may be substituted (for example, an alkynyl that has the carbon number of 2 to 10 such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl, 3-hexynyl or the like, preferably a lower (C2-6)alkynyl, or the like is exemplified);
(6) an aralkyl that may be substituted (for example, a phenyl-C1-4 alkyl (for example, benzyl, phenethyl or the like) or the like is exemplified); and
(7) an aryl that may be substituted (for example, phenyl, naphthyl or the like is exemplified), where examples of the substituents that may be possessed by (1) an alkyl that may be substituted, (2) a cycloalkyl that may be substituted, (3) an alkenyl that may be substituted, (4) a cycloalkenyl that may be substituted, (5) an alkynyl that may be substituted, (6) an aralkyl that may be substituted and (7) an aryl that may be substituted, which are described above, include a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a C1-4 alkyl that may be halogenated (for example, trifluoromethyl, methyl, ethyl or the like), a C1-6 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like, formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like) or the like, where the number of the substituents is preferably 1 to 3.
The hydroxyl group that may be substituted, which is indicated by R5xe2x80x2 and R6xe2x80x2, is exemplified by the hydroxyl group that may be possessed by, for example, (1) an alkyl that may be substituted (for example, a C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl or the like, preferably a lower (C1-6)alkyl, or the like is exemplified);
(2) a cycloalkyl that may be substituted (for example, a C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like);
(3) an alkenyl that may be substituted (for example, an alkenyl that has the carbon number of 2 to 10 such as allyl, crotyl, 2-pentenyl, 3-hexenyl or the like, preferably a lower (C2-6)alkenyl, or the like is exemplified);
(4) a cycloalkenyl that may be substituted (for example, an cycloalkenyl that has the carbon number of 3 to 7 such as 2-cyclopentenyl, 2-cyclohexenyl 2-cyclopentenylmethyl, 2-cyclohexenylmethyl or the like, or the like is exemplified);
(5) an aralkyl that may be substituted (for example, a phenyl-C1-4 alkyl (for example, benzyl, phenethyl or the like) or the like is exemplified);
(6) formyl or an acyl that may be substituted (for example, an alkanoyl that has the carbon number of 2 to 4 (for example, acetyl, propionyl, butyryl, isobutyryl or the like), an alkylsulfonyl that has the carbon number of 1 to 4 (for example, methanesulfonyl, ethanesulfonyl or the like) or the like is exemplified); and
(7) an aryl that may be substituted (for example, phenyl, naphthyl or the like is exemplified).
Examples of the substituents that may be possessed by (1) an alkyl that may be substituted, (2) a cycloalkyl that may be substituted, (3) an alkenyl that may be substituted, (4) a cycloalkenyl that may be substituted, (5) an aralkyl that may be substituted, (6) an acyl that may be substituted and (7) an aryl that may be substituted, which are described above, include a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a C1-4 alkyl that may be halogenated (for example, trifluoromethyl, methyl, ethyl or the like), a C1-6 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like, formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like) and the like, where the number of the substituents is preferably 1 to 3.
Also, in the above-mentioned formula, R5xe2x80x2 and R6xe2x80x2 may bind each other to form a cyclic ring group together with the adjacent phosphorus atom (preferably, a 5- to 7-membered cyclic ring). Such a cyclic ring may have substituents and examples of said substituents include a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a C1-4 alkyl that may be halogenated (for example, trifluoromethyl, methyl, ethyl or the like), a C1-6 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like, formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like) and the like, where the number of the substituents is preferably 1 to 3.
In the above-mentioned formula (I), a counter anion in the case where the phosphorus atom forms a phosphonium salt is exemplified by, in addition to an anion of a halogen atom (for example, Clxe2x88x92, Brxe2x88x92, Ixe2x88x92 or the like) or the like, an anion derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, an anion derived from an organic acid such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like and an anion derived from an acidic amino acid such as aspartic acid, glutamic acid and the like, where Clxe2x88x92, Brxe2x88x92, Ixe2x88x92 or the like is more preferable.
An amino group that may be substituted, which is indicated by R5xe2x80x2 and R6xe2x80x2, is exemplified by an amino group that may have 1 to 2 groups such as,
(1) an alkyl that may be substituted (for example, a C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl or the like, preferably a lower (C1-6)alkyl, or the like is exemplified);
(2) a cycloalkyl that may be substituted (for example, a C3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like);
(3) an alkenyl that may be substituted (for example, an alkenyl that has the carbon number of 2 to 10 such as allyl, crotyl, 2-pentenyl, 3-hexenyl or the like, preferably a lower (C2-6)alkenyl, or the like is exemplified);
(4) a cycloalkenyl that may be substituted (for example, an cycloalkenyl that has the carbon number of 3 to 7 such as 2-cyclopentenyl, 2-cyclohexenyl 2-cyclopentenylmethyl, 2-cyclohexenylmethyl or the like, or the like is exemplified);
(5) formyl or an acyl that may be substituted (for example, an alkanoyl that has the carbon number of 2 to 4 (for example, acetyl, propionyl, butyryl, isobutyryl or the like), an alkylsulfonyl that has the carbon number of 1 to 4 (for example, methanesulfonyl, ethanesulfonyl or the like) or the like is exemplified); and
(6) an aryl that may be substituted (for example, phenyl, naphthyl or the like is exemplified).
Examples of the substituents that may be possessed by (1) an alkyl that may be substituted, (2) a cycloalkyl that may be substituted, (3) an alkenyl that may be substituted, (4) a cycloalkenyl that may be substituted, (5) an acyl that may be substituted and (6) an aryl that may be substituted, which are described above, include a halogen (for example, fluorine, chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl group, the thiol group that may be substituted (for example, thiol, a C1-4 alkylthio or the like), an amino group that may be substituted (for example, amino, a mono-C1-4 alkylamino, a di-C1-4 alkylamino, a 5- to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like, or the like), the carboxyl group that may be esterified or amidated (for example, carboxyl, a C1-4 alkoxycarbonyl, carbamoyl, a mono-C1-4 alkylcarbamoyl, a di-C1-4 alkylcarbamoyl or the like), a C1-4 alkyl that may be halogenated (for example, trifluoromethyl, methyl, ethyl or the like), a C1-6 alkoxyl that may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like, formyl, a C2-4 alkanoyl (for example, acetyl, propionyl or the like), a C1-4 alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like) and the like, where the number of the substituents is preferably 1 to 3.
The substituents for xe2x80x9can amidino group that may be substitutedxe2x80x9d and xe2x80x9ca guanidino group that may be substitutedxe2x80x9d are exemplified by substituents similar to those for xe2x80x9can amino group that may be substituted, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxidexe2x80x9d that is indicated by R2.
It is preferable that R2 is (1) an amino group that may be substituted, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxide, (2) a nitrogen-containing, heterocyclic ring group that may be substituted and may contain the sulfur atom or the oxygen atom as a ring-constituting atom, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxide, (3) an amidino group that may be substituted or (4) a guanidino group that may be substituted and it is more preferable that R2 is an amino group that may be substituted, where the nitrogen atom may be converted into a quaternary ammonium or the N-oxide, or the like. Also, R2 may be an amidino group that may be substituted or a guanidino group that may be substituted.
It is more preferable that R2 is xe2x80x94NRRxe2x80x3 or xe2x80x94N+RRxe2x80x2Rxe2x80x3 (wherein each of R, Rxe2x80x2 and Rxe2x80x3 indicates an aliphatic hydrocarbon group (an aliphatic-chain hydrocarbon group and an aliphatic, cyclic hydrocarbon group) that may be substituted or an alicyclic (non-aromatic), heterocyclic ring group that may be substituted).
In the above-mentioned formula, xe2x80x9can aliphatic hydrocarbon group that may be substitutedxe2x80x9d and xe2x80x9can alicyclic, heterocyclic ring group that may be substitutedxe2x80x9d, which are indicated by R, Rxe2x80x2 and Rxe2x80x2, are exemplified by substituents similar to xe2x80x9can aliphatic hydrocarbon group that may be substituted (for example, an alkyl, a cycloalkyl, an alkenyl, a cycloalkenyl or the like, each of which may be substituted)xe2x80x9d and xe2x80x9can alicyclic, heterocyclic ring group that may be substituted (for example, a 5- to 6-membered, non-aromatic, heterocyclic ring that may be substituted or the like)xe2x80x9d, which are exemplified by as the substituents that may be possessed by xe2x80x9can amino group that may be substitutedxe2x80x9d indicated by R2.
Especially, as for R and Rxe2x80x2, an aliphatic hydrocarbon group that may be substituted (for example, an alkyl, an alkenyl or the like, each of which may be substituted) is preferable, a C1-6 alkyl group that may be substituted is more preferable and the methyl that may be substituted is particularly preferable.
It is preferable that Rxe2x80x3 is an aliphatic hydrocarbon group that may be substituted (preferably, a C3-8 cycloalkyl group that may be substituted; more preferably, a cyclohexyl that may be substituted) or an alicyclic, heterocyclic ring group that may be substituted (preferably, a saturated alicyclic, heterocyclic ring group that may be substituted (preferably, a 6-membered cyclic ring group); more preferably, tetrahydropyranyl that may be substituted, tetrahydrothiopyranyl that may be substituted or piperidyl that may be substituted; and particularly preferably, tetrahydropyranyl that may be substituted).
The following compounds are preferable as the compounds represented by formula (I).
N-[4-[N-Methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[2-(4-propoxyphenyl)ethoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide;
N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(3-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide;
N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(2-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide;
N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(4-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide;
N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(4-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide;
N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[[4-(propoxymethyl)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide;
N-[1-(tetrahydropyran-4-yl)piperidin-4-yl]-7-(4-phenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide;
N-[4-[(2-imidazolin-2-yl)methyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide;
N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(4-propoxyphenyl)methoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide;
N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[(4-propoxyethoxyphenyl)methoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide;
N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-[3-(4-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide; and the like.
As for a salt of any of the compounds represented by formula (I) of the present invention, a pharmaceutically permissible salt is preferable and is exemplified by a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid and the like. Preferable examples of a salt with an inorganic base include an alkali metal salt such as the sodium salt, the potassium salt and the like; an alkaline earth metal salt such as the calcium salt, the magnesium salt and the like; as well as the aluminum salt, the ammonium salt and the like. Preferable examples of a salt with an organic base include salts with any of trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine and the like. Preferable examples of a salt with an inorganic acid include salts with any of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of a salt with an organic acid include salts with any of formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Preferable examples of a salt with a basic amino acid include salts with any of arginine, lysine, ornithine and the like, and preferable examples of a salt with an acidic amino acid include salts with any of aspartic acid, glutamic acid and the like. The compounds represented by formula (I) of the present invention may be in the form of hydrates or may be in the form of non-hydrates. Also, in the case where any of the compounds represented by formula (I) of the present invention exists in configurational isomers, diastereomers, conformers or the like, they can be separated into each isomer according to a well-known, separation/purification means. Also, in the case where any of the compounds represented by formula (I) of the present invention is in the form of racemates, they may be separated according to a conventional optical resolution means into the (S) form and the (R) form, where each of the optically active compounds and the racemates is encompassed in the present invention.
The prodrug of any of the compounds represented by formula (I) to be employed in the present invention or a salt thereof [hereinafter, it may be designated as compound (I).] refers to a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, namely, a compound that is converted into compound (I) by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically, and a compound that is converted into compound (I) by hydrolysis with gastric acid or the like. Examples of the prodrug of compound (I) include a compound, wherein the amino group in compound (I) is acylated, alkylated or phosphorylated (for example, a compound, wherein the amino group in compound (I) is converted into eicosanoylamino, alanylamino, pentylaminocarbonylamino, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylamino, tetrahydrofuranylamino, pyrrolidylmethylamino, pivaloyloxymethylamino or tert-butylamino, or the like); a compound, wherein the hydroxyl group in compound (I) is acylated, alkylated, phosphorylated or converted into the borate (for example, a compound, wherein the hydroxyl group in compound (I) is converted into acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, or dimethylaminomethylcarbonyloxy, or the like); a compound, wherein the carboxyl group in compound (I) is esterified or amidated (for example, a compound, wherein the carboxyl group in compound (I) is subjected to ethyl esterification, phenyl esterification, carboxyoxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl esterification, cyclohexyloxycarbonyl esterification, or conversion into the methyl amide, or the like); and the like. These compounds can be produced from compound (I) according to a well-known method.
Moreover, the prodrug of compound (I) may be a compound that is converted into compound (I) under a physiological condition as described in xe2x80x9cDevelopment of Drugsxe2x80x9d, Volume 7, Molecular Design, Hirokawa Shoten, 1990; pages 163-198.
Also, compound (I) may be labeled with an isotope (for example, 3H, 14C, 35S, 125I or the like) or the like.
Any of the compounds represented by formula (I) of the present invention or a salt thereof (hereinafter, in the case where it abbreviated as compound (I), a salt thereof as well as any of the compounds represented by formula (I) and a salt thereof shall be included) can be alone, or by compounding with a pharmaceutically permissible carrier, orally or parenterally administered as a solid formulation such as a tablet, a capsule, a granule, a powder or the like; or a liquid formulation such as a syrup, an injection or the like.
The parenterally administered form is exemplified by an injection, a drip, a suppository, a pessary and the like, where a pessary is particularly useful for the prophylaxis of the HIV infectious diseases.
As for the pharmaceutically permissible carrier, any of a variety of organic or inorganic carrier substances, which have been conventionally employed as formulation materials, are used and compounded as a bulking agent, a lubricant, a binding agent and a disintegrator in a solid formulation; a vehicle, a solubilizing agent, a suspending agent, an isotonicity agent, a buffering agent and an analgesic in a liquid formulation. Also, as needed, formulation excipients such as a preservative, an antioxidant, a stabilizer, a coloring agent, a sweetening agent and the like can be used. Preferable examples of the bulking agent include, for example, lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include, for example, magnesium stearate, potassium stearate, talc, colloidal silica and the like. Preferable examples of the binding agent include, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and the like. Preferable examples of the disintegrator include, for example, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch and the like. Preferable examples of the vehicle include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferable examples of the suspending agent include, for example, a surface active agent such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate and the like; a hydrophilic, high molecular weight substance such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like, and the like. Preferable examples of the isotonicity agent include, for example, sodium chloride, glycerin, D-mannitol, and the like. Preferable examples of the buffering agent include, for example, a buffer solution of a phosphate, an acetate, a carbonate or a citrate and the like. Preferable examples of the analgesic include, for example, benzyl alcohol and the like. Preferable examples of the preservative include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include, for example, sulfites, ascorbic acid and the like.
Any of the compounds represented by formula (I) of the present invention or a salt thereof may be employed in combination with another prophylactic/therapeutic agent of HIV infectious diseases (particularly a prophylactic/therapeutic agent of AIDS). In this case, these drugs can be formulated by compounding, separately or at the same time, with a pharmacologically permissible carrier, a bulking agent, a binding agent, a diluent and the like, and the resulting preparation can be orally or parenterally administered as the pharmaceutical composition for the prophylaxis and/or therapeutics. In the case where the drugs are formulated separately, the separately formulated preparations can be administered by admixing by the use of a diluent at the time of usage, whereas each of the separately formulated preparations may be administered to the same subject at the same time or separately with a time difference. A kit product for administering the separately formulated preparations by admixing by the use of a diluent at the time of usage (for example, a kit for injection comprising ampoules, each containing a particular drug, and a diluent for dissolving 2 or more kinds of drugs by admixing at the time of usage, or the like), a kit product for administering each of the separately formulated preparations to the same subject at the same time or separately with a time difference (for example, a kit for tablets, which encloses the tablets, each containing a particular drug, in a same bag or separate bags, as needed, fitted with a time field where the times for administration of the drugs are described, and allows to administer 2 or more kinds of drugs at the same time or separately with a time difference, or the like) and the like are encompassed in the pharmaceutical compositions of the present invention.
Specific examples of other prophylactic/therapeutic agents of HIV infectious diseases, which are to be employed in combination with the compounds represented by formula (I) of the present invention or salts thereof, include nucleic acid reverse transcriptase inhibitors such as zidovudine, didanosine, zalcitabine, lamivudine, stavudine, abacavir, adefovir, adefovir dipivoxil, fozivudine tidoxil and the like; non-nucleic acid reverse transcriptase inhibitors such as nevirapine, delavirdine, efavirenz, loviride, immunocal, olitipraz and the like (contain drugs, which have an antioxidant action, such as immunocal, olitipraz and the like); protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, palinavir, lasinavir and the like; and the like.
As for the nucleic acid reverse transcriptase inhibitors, zidovudine, didanosine, zalcitabine, lamivudine, stavudine and the like are preferable, as for non-nucleic acid reverse transcriptase inhibitors, nevirapine, delavirdine and the like are preferable and as for the protease inhibitors, saquinavir, ritonavir, indinavir, nelfinavir and the like are preferable.
Processes for the production of the compounds represented by formula (I) or salts thereof are shown in the following.
The compounds represented by formula (I) or salts thereof can be produced according to the well-known processes. For instance, they can be produced according to the following processes. Also, the compounds represented by formula (I) or salts thereof can be produced according to the process described in Japanese Patent Kokai Publication No. 1996-73476 or a modified process thereof.
Compounds, which are to be used in each of the following production processes, may form salts similar to compounds (I), as far as the reactions are not disturbed.
Also, in the case where a compound to be used as the raw material has an amino group, the carboxyl group and the hydroxyl group as substituents in each of the following reactions, such protective groups that are employed in general in the peptide chemistry may be introduced to these groups, where the objective compounds can be obtained by removal of the protecting groups after the reactions, as needed.
As for the protective group for an amino group, there is employed, for example, a C1-6 alkylcarbonyl (for example, acetyl, propionyl or the like), formyl, a phenylcarbonyl, a C1-6 alkyloxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl or the like), a phenyloxycarbonyl (for example, benzoxycarbonyl or the like), a C7-10 aralkyloxycarbonyl (for example, benzyloxycarbonyl or the like), trityl, phthaloyl or the like, each of which may have substituents. As for these substituents, there is employed a halogen atom (for example, fluorine, chlorine, bromine, iodine or the like), a C1-6 alkylcarbonyl (for example, acetyl, propionyl, butyryl or the like), the nitro group or the like, where the number of the substituents is about 1 to 3.
As for the protective group for the carboxyl group, there is employed, for example, a C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or the like), phenyl, trityl, silyl or the like, each of which may have substituents. As for these substituents, there is employed a halogen atom (for example, fluorine, chlorine, bromine, iodine or the like), a C1-6 alkylcarbonyl (for example, acetyl, propionyl, butyryl or the like), formyl, the nitro group or the like, where the number of the substituents is about 1 to 3.
As for the protective group for the hydroxyl group, there is employed, for example, a C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or the like), phenyl, a C7-10 aralkyl (for example, benzyl or the like), a C1-6 alkylcarbonyl (for example, acetyl, propionyl or the like), formyl, a phenylcarbonyl, a C7-10 aralkyloxycarbonyl (for example, benzyloxycarbonyl or the like), pyranyl, furanyl, silyl or the like, each of which may have substituents. As for these substituents, there is employed a halogen atom (for example, fluorine, chlorine, bromine, iodine or the like), a C1-6 alkyl, phenyl, a C7-10 aralkyl, the nitro group or the like, where the number of the substituents is about 1 to 4.
Also, as for the methods for introduction and removal of the protective groups, the well-known methods or modified methods thereof [for example, methods described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (by J. F. W. McOmie et al., Plenum Press Company) are employed, where methods to treat with, for example, an acid, a base, a ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like are employed as the methods for removal.
[Method A]
Compound (I) or a salt thereof can be produced, according to the reaction shown below, by reacting compound [II] or a salt thereof with compound [III] or a salt thereof. 
[wherein a group, which reacts with the substituent Xb2 in compound [III] or a salt thereof to form X2, is indicated by Xa2 (for example, the carboxyl group or the like) and a group, which reacts with the substituent Xa2 in compound [II] or a salt thereof to form X2, is indicated by Xb2 (for example, the amino group or the like) and other symbols have the same meanings as mentioned hereinabove.]
In the following is shown the production process in the case where Xa2 is the carboxyl group, Xb2 is the amino group and X2 is xe2x80x94COxe2x80x94NHxe2x80x94. 
[each symbol of the formula has the same meaning as mentioned hereinabove]
In the present method, compound [I-1] is produced be reacting a carboxylic acid derivative [II-1] with an amine derivative.[III-1].
The condensation reaction of [II-1] and [III-1] is carried out according to a conventional means for peptide synthesis. Said means for peptide synthesis may be followed by an optional known method, a method described in, for example, M. Bodansky and M. A. Ondetti, Peptide Synthesis, Interscience, New York, 1996; F. M. Finn and K. Hofmann, The Proteins, Volume 2, H. Nenrath and R. L. Hillor, Ed., Academic Press Inc., New York, 1976; Nobuo Izumiya et al. xe2x80x9cBases and Experiments for Peptide Synthesisxe2x80x9d, Maruzen Kabushiki Kaisha, 1985, or the like, as exemplified by the azide method, the chloride method, the acid anhydride method, the mixed acid anhydride method, the DCC method, the active ester method, the method by the use of Woodward reagent K, the carbonyl diimidazole method, the oxidation-reduction method, the DCC/HONB method or the like, as well as the WSC method, the method by the use of diethyl cyanophosphonate or the like. The present condensation reaction can be carried out in a solvent. The solvent is exemplified by, for example, N,N-dimethylformamide, dimethyl sulfoxide, pyridine, chloroform, dichloromethane, tetrahydrofuran, dioxane, acetonitrile or an adequate mixture of these solvents. The reaction temperature is usually about xe2x88x9220xc2x0 C. to about 50xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about 30xc2x0 C. The reaction time is usually about 2 hour to about 40 hours. The thus-obtained compound (I-1) can be subjected to isolation and purification according to the known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, trans-solubilization, chromatography and the like.
[Method B]
[1] In the case where R2xe2x80x3 represented in compound [I-2] is, for example, a tertiary amine residue, quaternary compound
[Ixe2x80x2] can be produced by reacting compound [I-2] with a halogenated alkyl or a halogenated aralkyl. Herein, the halogen atom is exemplified by chlorine, bromine, iodine or the like, and a halogenated alkyl (for example, a halogenated, lower (C1-6)alkyl or the like) or a halogenated aralkyl (for example, a halogenated, lower (C1-4)alkylphenyl or the like) is used usually in an amount of about 1 to 5 moles per one mole of compound [I-2]. The present reaction can be carried out in an inactive solvent, as exemplified by, for example, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl acetamide or a mixed solvent thereof. The reaction temperature is a temperature range of about 10xc2x0 C. to about 160xc2x0 C., preferably about 20xc2x0 C. to about 120xc2x0 C. The reaction time is usually about one hour to about 100 hours, preferably, about 2 hours to about 40 hours. In addition, the present reaction is carried out preferably under an atmosphere of an inert gas (for example, nitrogen, argon or the like).
[2] In the case where R2xe2x80x3 represented in compound [I-2] is, for example, a secondary amine residue, tertiary compound
[Ixe2x80x2] can be produced by reacting compound [I-2] with a halogenated alkyl or a halogenated aralkyl. Herein, the halogen atom is exemplified by chlorine, bromine, iodine or the like, and a halogenated alkyl or a halogenated aralkyl is used usually in an amount of about 1 to 2 moles per one mole of compound [I-2]. This reaction can be allowed to proceed smoothly, as needed, by addition of an about equimolar amount to 3 molar amount of a base such as triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or the like, and further by addition of sodium iodide, potassium iodide or the like.
The present tertiary amination reaction can be carried out in an inactive solvent, as exemplified by, for example, methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine or the like, or a mixed solvent thereof. The reaction temperature is a temperature range of about 0xc2x0 C. to about 180xc2x0 C. for about one hour to about 40 hours. In addition, the present reaction is carried out preferably under an atmosphere of an inert gas (for example, nitrogen, argon or the like).
[3] In the case where R2xe2x80x3 represented in compound [I-2] is, for example, a secondary amine residue, tertiary compound
[Ixe2x80x2] can be produced by reacting compound [I-2] with an aldehyde compound in the presence of a reductive amination reagent such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride or the like. It is preferable that the reaction conditions of the present reductive amination reaction are altered depending on the reagent to be used, where, for instance, in the case where sodium triacetoxyborohydride is used, the reaction can be carried out in an inactive solvent, as exemplified by, for example, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran (THF), diethyl ether, dioxane, acetonitrile, dimethylformamide (DMF) or the like, or a mixed solvent thereof. The present reagent is used in an amount of about 1 to 2 molar equivalents per one mole of compound [I-2]. The reaction is carried out usually at a temperature range of about 0xc2x0 C. to about 80xc2x0 C. for about one hour to about 40 hours. In addition, the present reaction is carried out preferably under an atmosphere of an inert gas (for example, nitrogen, argon or the like).
[4] In the case where R2xe2x80x3 represented in compound [I-2] is, for example, a sulfide residue or a tertiary amine residue, compound [Ixe2x80x2] having the sulfinyl group, the sulfonyl group or the amine oxide group can be produced by reacting compound [I-2] with an oxidizing agent such as m-chloroperbenzoic acid, perbenzoic acid, paranitroperbenzoic acid, magnesium monoperoxyphthalate, peracetic acid, hydrogen peroxide, sodium periodate, potassium periodate or the like. It is preferable that the reaction conditions of this oxidation reaction are altered depending on the oxidizing reagent to be used, where, for instance, in the case where m-chloroperbenzoic acid is used, the reaction can be carried out in an inactive solvent, as exemplified by, for example, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, acetone, ethyl acetate or the like, or a mixed solvent thereof. The oxidizing reagent is used in an amount of about 1 to 3 molar equivalents per one mole of compound [I-2]. The reaction is carried out usually at a temperature range of about xe2x88x9220xc2x0 C. to about 80xc2x0 C., (preferably, about xe2x88x9225xc2x0 C. to about 25xc2x0 C. for about one hour to about 40 hours.
[Method C] 
V in compound [IV] indicates a halogen atom (for example, chlorine, bromine, iodine or the like) or a sulfonyloxy group (the methanesulfonyloxy group, the trifluoromethanesulfonyloxy group, the benzenesulfonyloxy group or the toluenesulfonyloxy group) and other symbols indicate the same meanings as indicated hereinabove.
[1] Quaternary compound [Ixe2x80x2] can be produced by reacting compound [IV] with a tertiary amine. The present reaction can be carried out in an inactive solvent, as exemplified by, for example, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl acetamide or the like, or a mixed solvent thereof. The tertiary amine is used in an amount of about 1 to 3 moles per one mole of compound [IV]. The present reaction is carried out at a temperature range of about 10xc2x0 C. to about 120xc2x0 C. for about one hour to about 40 hours. In addition, the present reaction is carried out preferably under an atmosphere of an inert gas (for example, nitrogen, argon or the like).
[2] Quaternary compound [Ixe2x80x2] can be produced by reacting compound [IV] with a tertiary phosphine. The present reaction can be carried out in an inactive solvent, as exemplified by, for example, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, dimethylformamide (DMF) or the like, or a mixed solvent thereof. The tertiary phosphine is used in an amount of about 1 to 2 moles per one mole of compound [IV]. The present reaction is carried out at a temperature range of about 20xc2x0 C. to about 150xc2x0 C. for about one hour to about 50 hours. In addition, the present reaction is carried out preferably under an atmosphere of an inert gas (for example, nitrogen, argon or the like).
[3] Compound [Ixe2x80x2] having a secondary or tertiary amino group or a thio group can be produced by reacting compound [IV] with a primary or secondary amine compound or a thiol compound. The primary or secondary amine compound or the thiol compound is used usually in an amount of about 1 to 3 moles per one mole of compound [IV]. This reaction can be allowed to proceed smoothly, as needed, by addition of an about equimolar amount to 3 molar amount of a base such as triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or the like, and further by addition of sodium iodide, potassium iodide or the like. The present substitution reaction can be carried out in an inactive solvent, as exemplified by, for example, methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine or the like, or a mixed solvent thereof. The reaction is carried out at a temperature range of about xe2x88x9210xc2x0 C. to about 180xc2x0 C. for about one hour to about 40 hours. In addition, the present reaction is carried out preferably under an atmosphere of an inert gas (for example, nitrogen, argon or the like).
[Method D] 
[1] Compound [V] [wherein Vxe2x80x2 indicates a halogen atom (for example, bromine, iodine or the like) or a sulfonyloxy group (the trifluoromethanesulfonyloxy group or the like) and other symbols indicate the same meanings as indicated hereinabove] is subjected to, for example, the Suzuki reaction [a cross condensation reaction of an arylboric acid and, for example, an aryl halide or an aryloxytrifluoromethanesulfonate by the use of a palladium catalyst; A. Suzuki, et al., Synth. Commun. 1981, 11, 513] to be able to produce compound [Ixe2x80x3], wherein X1 indicates a bond and R1 indicates a 5- to 6-membered, cyclic ring aromatic group. Compound [Ixe2x80x3] can be obtained by the use of an arylboric acid in an about equimolar amount to 1.5 molar amount per one mole of compound [V].
Also, compound [V] is subjected to, for example, a cross condensation reaction with an arylacetylene compound in the presence of a palladium catalyst [dichlorobis(triphenylphosphine)palladium or the like] [K. S. Y. Lau, et al., J. Org. Chem. 1981, 46, 2280; J. W. Tilley, S. Zawoisky, et al., J. Org. Chem. 1988, 53, 386] to be able to produce compound [Ixe2x80x3] having an acetylenic bond, wherein X1 indicates xe2x80x94Cxe2x89xa1Cxe2x80x94. Compound [Ixe2x80x3] can be obtained by the use of an arylacetylene compound, usually, in an about equimolar amount to 2 molar amount per one mole of compound [V].
[2] Compound [V] [wherein Vxe2x80x2 indicates the hydroxyl group and other symbols indicate the same meanings as indicated hereinabove] is subjected to, for example, the Mitsunobu reaction [the etherification reaction by the use of a condensing agent such as, for example, triphenylphosphine and diethyl azodicarboxylate; O. Mitsunobu, et al., Synthesis, 1981, 1] to be able to produce compound [Ixe2x80x3] having an ether bond. Compound [Ixe2x80x3] can be obtained by the use of the corresponding alcohol compound or phenol compound in an about equimolar amount to 3 molar amount per one mole of compound [V].
In addition, compound [Ixe2x80x3] having an ether bond can be produced also by the etherification reaction of compound [V] with a reactive compound such as a halo (chloro, iodo or the like) compound, a tosylate compound, a mesylate compound or the like. Said reactive compound is used usually in an about equimolar amount to 3 molar amount per one mole of compound [V]. This reaction can be allowed to proceed smoothly, as needed, by addition of an about equimolar amount to 3 molar amount of a base such as triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or the like, and further by addition of sodium iodide, potassium iodide or the like. The present substitution reaction can be carried out in an inactive solvent, as exemplified by, for example, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine or the like, or a mixed solvent thereof. The reaction is carried out at a temperature range of about xe2x88x9210xc2x0 C. to about 180xc2x0 C. for about one hour to about 40 hours. In addition, the present reaction is carried out preferably under an atmosphere of an inert gas (for example, nitrogen, argon or the like).
[3] Compound [V] [wherein Vxe2x80x2 indicates the carbonyl group or a phosphonium salt, each of which may be substituted, or a phosphorous acid ester residue and other symbols indicate the same meanings as indicated hereinabove] is subjected to, for example, the Wittig reaction [A. Maercker, Org. React. 14, 270 (1965)] or the Wittig-Horner-Emmons reaction [J. Boutagy, R. Thomas, Chem. Rev., 74, 87 (1974)] to be able to produce compound [Ixe2x80x3] having a vinyl bond. The corresponding carbonyl compound or phosphonium salt, or the phosphorous acid ester residue is used usually, in an about equimolar amount to 1.5 molar amount per one mole of compound [V].
[Method E] 
[1] First, compound [VI] [wherein Vxe2x80x3 indicates the cyano group and other symbols indicate the same meanings as indicated hereinabove] is reacted with a lower alcohol such as methanol, ethanol, propanol or the like in the presence of an acid such as hydrochloric acid or the like to obtain an imidate compound. The present reaction is carried out usually by the use of an excess amount of the above-mentioned alcohol at a temperature range of about xe2x88x9210xc2x0 C. to about 50xc2x0 C. for about one hour to about 40 hours. Also, the present reaction can be carried out in an inactive solvent, as exemplified by, for example, diethyl ether, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane or the like, or a mixed solvent thereof.
Next, the thus-obtained imidate compound is subjected to the substitution reaction with a primary or secondary amine compound to be able to produce an amidine compound [Ixe2x80x2xe2x80x3]. The primary or secondary amine compound is used usually in an amount of about 1 to 5 moles per one mole of the imidate compound. This reaction can be allowed to proceed smoothly, as needed, by addition of an about equimolar amount to 3 molar amount of a desalting agent such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate or the like. The present substitution reaction can be carried out in an inactive solvent, as exemplified by, for example, methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine or the like, or a mixed solvent thereof. The reaction is carried out at a temperature range of about 0xc2x0 C. to about 150xc2x0 C. for about one hour to about 50 hours. In addition, the present reaction is carried out preferably under an atmosphere of an inert gas (for example, nitrogen, argon or the like).
[2] Compound [VI] [wherein Vxe2x80x3 indicates the amino group and other symbols indicate the same meanings as indicated hereinabove] is subjected to the substitution reaction with an S-alkyl (for example, methyl, ethyl or the like)-isothiourea compound to be able to produce a guanidine compound [Ixe2x80x2xe2x80x3]. The S-alkyl-isothiourea compound is used usually in an equimolar amount to about 2 molar amount per one mole of compound [VI]. This reaction can be allowed to proceed smoothly, as needed, by addition of an about equimolar amount to 3 molar amount of a desalting agent such as triethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate or the like. The present substitution reaction can be carried out in an inactive solvent, as exemplified by, for example, methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine or the like, or a mixed solvent thereof. The reaction is carried out at a temperature range of about 0xc2x0 C. to about 150xc2x0 C. for about one hour to about 50 hours. In addition, the present reaction is carried out preferably under an atmosphere of an inert gas (for example, nitrogen, argon or the like).
The thus-obtained compound (I) can be subjected to isolation and purification according to the known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, trans-solubilization, chromatography and the like.
Compound [II-1] to be used as the starting material can be produced according to a known process (for instance, the process described in Japanese Patent Kokai Publication No. 1996-73476 or the like) or a modified process thereof, where, for instance, the material can be produced according to the process shown in reaction scheme I as well as the process indicated in Reference Examples described hereinafter or a modified process thereof. 
[wherein R9 indicates a C1-4 alkyl group, Yxe2x80x3 indicates a bivalent group without an unsaturated bond, through which ring B forms a 5- to 7-membered cyclic ring, and other symbols indicate the same meanings as indicated hereinabove.]
In the present process, first, a compound represented by formula [VII] is heated with polyphosphoric acid, or compound [VII] is treated with thionyl chloride, oxalyl chloride, phosphorus pentachloride or the like to be converted into the corresponding acid chloride, which is then subjected to cyclization by the conventional Friedel-Crafts reaction to produce compound [III]. Next, compound [III] is reacted with a carbonic acid ester in the presence of a base to produce a keto ester [IX]. Compound [IX] is converted into compound [X] by catalytic hydrogenation or the reduction reaction with sodium borohydride or the like. Compound [X] is subjected to the dehydration reaction according to a conventional method to produce an unsaturated carboxylic acid ester [XI], which is then subjected to the ester-hydrolysis reaction to produce an unsaturated carboxylic acid [IIxe2x80x2].
Of compound [II] to be used as the starting material, a compound wherein Xa2 is not the carboxylic acid (for example, compound [II] wherein Xa2 is the chlorosulfonyl group, the hydroxymethyl group, a halo (chloro or bromo) methyl group, the formyl group, the acetamido group or the like) can be produced according to the process shown in reaction scheme II as well as the process indicated in Reference Examples described hereinafter or a modified process thereof. 
[each of the symbols in the formula indicates the same meaning as indicated hereinabove.]
The sulfonyl chloride compound [IIxe2x80x2a] can be produced by subjecting a compound represented by formula [VIII] to the reduction according to a conventional method (the reduction with sodium borohydride or by catalytic hydrogenation or the like) followed by the dehydration reaction to produce compound [XII], which is subjected to the reaction with sulfuryl chloride.
The hydroxymethyl compound (IIxe2x80x2b] can be produced by subjecting an ester compound represented by formula [XI] to the reduction according to a conventional method (the reduction with sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride (DIBAL) or the like). The thus-obtained hydroxymethyl compound [IIxe2x80x2b] is subjected to the chlorination reaction with thionyl chloride or the like, or to the bromination reaction with triphenylphosphine-carbon tetrabromide or the like to be able to produce the halomethyl compound [IIxe2x80x2c].
Also, the formyl compound [IIxe2x80x2d] can be produced by subjecting a hydroxymethyl compound to the oxidation reaction with activated manganese dioxide or the like.
Furthermore, the amine compound [IIxe2x80x2f] can be produced by subjecting a carboxylic acid compound represented by formula [IIxe2x80x2] to the rearrangement reaction according to a conventional method with, for example, diphenylphosphoric acid amide (DPPA)-t-butanol to produce a urethane compound [IIxe2x80x2e], which is then subjected to the acid-hydrolysis reaction.
The thus-obtained compound [IIxe2x80x2a], [IIxe2x80x2b], [IIxe2x80x2c], [IIxe2x80x2d], [IIxe2x80x2e] or [IIxe2x80x2f] and a compound represented by formula [III] are subjected to a variety of the above-mentioned reactions such as the amidation reaction, the tertiary amination reaction, the reductive amination reaction, the vinylation reaction, the etherification reaction, the alkylation (aralkylation) reaction and the like to be able to be converted into the compounds represented by formula (I) wherein X2 is not the carbonylamido group.
In addition, compound [III-1] also can be produced according to a known process (for instance, the process described in Japanese Patent Kokal Publication No. 1996-73476 or the like) or a modified process thereof, where, for instance, the material can be produced according to the process shown in reaction scheme III as well as the process indicated in Reference Examples described hereinafter or a modified process thereof. 
[each of the symbols in the formula indicates the same meaning as indicated hereinabove.]
The reduction reaction of compound [III] can be carried out according to the well-known methods. For instance, the reduction with a metal, the reduction with a metal hydride, the reduction with a metal hydride complex, the reduction with diborane and a substituted diborane, catalytic hydrogenation or the like. In other words, this reaction is carried out by treating compound [XIII] with a reducing agent. The reducing agent is exemplified by a metal and a metallic salt such as a metal such as reduced iron, zinc powder or the like, an alkaline metal borohydride (for example, sodium borohydride, lithium borohydride or the like), a metal hydride complex such as lithium aluminum hydride or the like, a metal hydride such as sodium hydride or the like, an organotin compound (such as triphenyltin hydride or the like), a nickel compound, a zinc compound or the like, a catalytic hydrogenation agent by the use of a transition-metal catalyst such as platinum, rhodium or the like and hydrogen, diborane and the like, where a catalytic hydrogenation agent by the use of a transition-metal catalyst such as platinum, rhodium or the like and hydrogen as well as the reduction with a metal such as reduced iron or the like are advantageously carried out. The reaction is carried out in an organic solvent that is inert to the reaction. As for said solvent to be used, there is selected appropriately, depending on the kind of the reducing agent, from, for example, benzene, toluene, xylene, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, diethyl ether, tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol, 2-methoxyethanol, N,N-dimethylformamide, acetic acid or a mixed solvent thereof. The reaction temperature is about xe2x88x9220xc2x0 C. to about 150xc2x0 C., particularly preferably, about xe2x88x920xc2x0 C. to about 100xc2x0 C., and the reaction hour is about one hour to about 24 hours.
The thus-obtained compound (IIIxe2x80x2) can be subjected to isolation and purification according to the known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, trans-solubilization, chromatography and the like.
Because any of the compounds represented by formula (I) of the present invention or a salt thereof possesses a potent CCR5 antagonistic action, it is employed for the prophylaxis and the therapeutics of a variety of HIV infectious diseases in the human, for example, AIDS. Any of the compounds represented by formula (I) of the present invention or a salt thereof is of a low toxicity and can be employed safely.
Any of the compounds represented by formula (I) of the present invention or a salt thereof can be employed as a CCR5 antagonistic agent, for instance, as a prophylactic and therapeutic agent of AIDS and a depressant against the pathologic progress of AIDS.
The daily dosage of any of the compounds represented by formula (I) or a salt thereof is different depending on the condition and the weight of the patient as well as the administration method, where, in the case of the oral administration, the dosage as the active ingredient [any of the compounds represented by formula (I) or a salt thereof] per an adult (a body weight of 50 kg) is about 5 mg to 1000 mg, preferably about 10 mg to 600 mg, further preferably about 10 mg to 300 mg, particularly preferably about 15 to 150 mg, where the daily dosage is administered once or with being divided in 2 to 3 times.
Also, in the case where any of the compounds represented by formula (I) or a salt thereof is employed in combination with a reverse transcriptase inhibitor and/or a protease inhibitor, the dosage of the reverse transcriptase inhibitor or the protease inhibitor is appropriately selected, for example, in a range of more than about 1/200 to 1/2 fold and less than 2 to 3 fold on the basis of the ordinary dosage. Furthermore, in the case where 2 or more kinds of drugs are employed in combination, when a drug affects the metabolism of other drugs, the dosage of each of the drugs is appropriately modulated, but the dosage of each of the drugs in the case of the administration as a single formulation is employed in general.
The ordinary dosages of the representative reverse transcriptase inhibitors and protease inhibitors are indicated, for instances, in the following.
Zidovudine: 100 mg
Didanosine: 125 to 200 mg
Zalcitabine: 0.75 mg
Lamivudine: 150 mg
Stavudine: 30 to 40 mg
Saquinavir: 600 mg
Ritonavir: 600 mg
Indinavir: 800 mg
Nelfinavir: 750 mg
In addition, in the following are shown the specific embodiments for the case where any of the compounds represented by formula (I) or a salt thereof is employed in combination with the reverse transcriptase inhibitor and/or the protease inhibitor.
[1] About 10 to 300 mg of any of the compounds represented by formula (I) or a salt thereof per an adult (a body weight of 50 kg) is administered to the same subject in a pattern of combination with about 50 to 200 mg of zidovudine. Each of the drugs may be administered respectively at the same time, or may be administered at a time difference within 12 hours.
[2] About 10 to 300 mg of any of the compounds represented by formula (I) or a salt thereof per an adult (a body weight of 50 kg) is administered to the same subject in a pattern of combination with about 300 to 1200 mg of saquinavir. Each of the drugs may be administered respectively at the same time, or may be administered at a time difference within 12 hours.